Orexin, Sleep, Sympathetic Neural Activity, and Cardiovascular Function

Inadequate sleep duration and quality are associated with reduced cardiovascular health and increased mortality. Experimental evidence points to the sympathetic nervous system as a key mediator in the observed relationship between poor sleep and cardiovascular dysfunction. However, brain mechanisms underpinning the impaired sympathetic function associated with poor sleep remain unclear. Recent evidence suggests the central orexin system, particularly orexins A and B and their receptors, have a key regulatory role for sleep in animal and human models. While orexin system activity has been observed to significantly impact sympathetic regulation in animals, the extension of these findings to humans has been difficult due to an inability to directly assess orexin system activity in humans. However, direct measures of sympathetic activity in populations with narcolepsy and chronic insomnia, 2 sleep disorders associated with deficient and excessive orexin neural activity, have allowed indirect assessment of the relationships between orexin, sleep, and sympathetic regulation. Further, the recent pharmaceutical development of dual orexin receptor antagonists for use in clinical insomnia populations offers an unprecedented opportunity to examine the mechanistic role of orexin in sleep and cardiovascular health in humans. The current review assesses the role of orexin in both sleep and sympathetic regulation from a translational perspective, spanning animal and human studies. The review concludes with future research directions necessary to fully elucidate the mechanistic role for orexin in sleep and sympathetic regulation in humans

Core Body Temperature Changes Prior to Sleep are Associated with Nocturnal Heart Rate Variability

Core body temperature (CBT) reductions occur prior to and during the sleep period, with the extent of pre-sleep reductions corresponding to sleep onset and quality. Pre-sleep reductions in CBT coincide with increased cardiac parasympathetic activity measured via heart rate variability (HRV), and while this appears to persist into the sleep period, individual differences in pre-sleep CBT decline and nocturnal HRV remain unexplored. The purpose of the current study was to assess the relationship between individual differences in pre-sleep CBT reductions and nocturnal heart rate (HR) and HRV in a population of 15 objectively poor sleeping adults (10 males, 5 females; age, 33 ± 4 years; BMI 27 ± 1 kg/m) with the hypothesis that blunted CBT rate of decline would be associated with elevated HR and reduced nocturnal HRV. Following an adaptation night, all participants underwent an overnight, in-laboratory sleep study with simultaneous recording of polysomnographic sleep including electrocardiography (ECG) and CBT recording. Correlations between CBT rate of change prior to sleep and nocturnal HRV were assessed. Blunted rate of CBT decline was significantly associated with increased heart rate (HR) in stage 2 (N2; R=.754, P=.001), stage 3 (N3; R=.748, P=.001), and rapid eye movement (REM; R=.735, P=.002). Similarly, blunted rate of CBT decline prior to sleep was associated with reduced HRV across sleep stages. These findings indicate a relationship between individual differences in pre-sleep thermoregulatory processes and nocturnal cardiac autonomic function in poor sleeping adults

Blood pressure and muscle sympathetic nerve activity are associated with trait anxiety in humans

Chronic anxiety is prevalent and associated with an increased risk of cardiovascular disease. Prior studies that have reported a relationship between muscle sympathetic nerve activity (MSNA) and anxiety have focused on participants with anxiety disorders and/or metabolic syndrome. The present study leverages a large cohort of healthy adults devoid of cardiometabolic disorders to examine the hypothesis that trait anxiety severity is positively associated with resting MSNA and blood pressure. Resting blood pressure (BP) (sphygmomanometer and finger plethysmography), MSNA (microneurography), and heart rate (HR; electrocardiogram) were collected in 88 healthy participants (52 males, 36 females, 25 ± 1 yr, 25 ± 1 kg/m2). Multiple linear regression was performed to assess the independent relationship between trait anxiety, MSNA, resting BP, and HR while controlling for age and sex. Trait anxiety was significantly correlated with systolic arterial pressure (SAP; r = 0.251, P = 0.018), diastolic arterial pressure (DAP; r = 0.291, P = 0.006), mean arterial pressure (MAP; r = 0.328, P = 0.002), MSNA burst frequency (BF; r = 0.237, P = 0.026), and MSNA burst incidence (BI; r = 0.225, P = 0.035). When controlling for the effects of age and sex, trait anxiety was independently associated with SAP (β = 0.206, P = 0.028), DAP (β = 0.317, P = 0.002), MAP (β = 0.325, P = 0.001), MSNA BF (β = 0.227, P = 0.030), and MSNA BI (β = 0.214, P = 0.038). Trait anxiety is associated with increased blood pressure and MSNA, demonstrating an important relationship between anxiety and autonomic blood pressure regulation.NEW & NOTEWORTHY Anxiety is associated with development of cardiovascular disease. Although the sympathetic nervous system is a likely mediator of this relationship, populations with chronic anxiety have shown little, if any, alteration in resting levels of directly recorded muscle sympathetic nerve activity (MSNA). The present study is the first to reveal an independent relationship between trait anxiety, resting blood pressure, and MSNA in a large cohort of healthy males and females devoid of cardiometabolic comorbidities

Evening Binge Alcohol Disrupts Cardiovagal Tone and Baroreflex Function During Polysomnographic Sleep

STUDY OBJECTIVES: Binge alcohol consumption is associated with increased cardiovascular risk. The effects of evening binge alcohol consumption (i.e., 4-5 beverages within two hours) on the vagal components of HRV and cardiovagal baroreflex sensitivity (cvBRS) during sleep remain largely equivocal. The present study examined the effects of evening binge alcohol consumption on nocturnal cardiac vagal tone and baroreflex sensitivity during stage N2, slow wave (SWS), and rapid eye movement (REM) sleep. We hypothesized that evening binge drinking would reduce HRV and cvBRS in each sleep stage. METHODS: Following a familiarization night within the laboratory, twenty-three participants were examined following a night of binge alcohol consumption and a fluid control (randomized, crossover design). A quality nocturnal beat-to-beat blood pressure signal was obtained in both conditions in 16 participants (7 men, 9 women; 25±1 years). RESULTS: Binge drinking reduced both the high frequency (HF) and time-domain components (i.e., pNN50 and RMSSD) of HRV in stage N2 sleep, SWS, and REM. In addition, cvBRS up-up (vagal activation) was reduced following binge alcohol consumption in stage N2 (21±3 vs. 15±3 ms/mmHg, P=0.035) and REM (15[11-28] vs. 11[9-18] ms/mmHg, P=0.009). Binge alcohol consumption reduced cvBRS down-down (vagal withdrawal) in stage N2 (23±2 vs. 14±2 ms/mmHg, P\u3c0.001), SWS (20[14-30] vs. 14[9-17] ms/mmHg, P=0.022), and REM (14[11-24] vs. 10[7-15] ms/mmHg, P=0.006). CONCLUSIONS: Evening binge alcohol consumption disrupts cardiac vagal tone and baroreflex function during nearly all sleep stages. These findings provide mechanistic insight into the potential role of binge drinking and alcohol abuse on cardiovascular risk

Blunted heart rate recovery to spontaneous nocturnal arousals in short-sleeping adults

Chronic insufficient sleep is a common occurrence around the world and results in numerous physiological detriments and consequences, including cardiovascular complications. The purpose of the present study was to assess the relationship between habitual total sleep time (TST) measured objectively via at-home actigraphy and heart rate (HR) reactivity to nocturnal cortical arousals. We hypothesized that short habitual TST would be associated with exaggerated cardiac reactivity to nocturnal cortical arousals. Participants included 35 healthy individuals [20 men, 15 women, age: 24 ± 1 yr, body mass index (BMI): 27 ± 1 kg/m], and were split using a median analysis into short-sleeping (SS; = 17) and normal-sleeping (NS; = 18) adults based on a minimum of 7 days of at-home actigraphy testing. All participants underwent a full overnight laboratory polysomnography (PSG) testing session, including continuous HR (electrocardiogram, ECG) sampling. HR reactivities to all spontaneous cortical arousals were assessed for 30 cardiac cycles following the onset of the arousal in all participants. Baseline HR was not significantly different between groups ( \u3e 0.05). Spontaneous nocturnal arousal elicited an augmented HR response in the SS group, specifically during the recovery period [(5.261,163.08) = 3.058, = 0.01, η = 0.09]. There were no significant differences in HR reactivity between sexes [(3.818,118.368) = 1.191, = 0.318]. These findings offer evidence of nocturnal cardiovascular dysregulation in habitual short sleepers, independent from any diagnosed sleep disorders. Short habitual sleep is associated with poor cardiovascular outcomes, but mechanisms remain equivocal. The present study used objectively measured habitual sleep via wrist actigraphy, and reports that habitual short sleepers have augmented heart rate recovery responses to spontaneous arousals as determined by gold-standard polysomnography. There were no reported sex differences. The augmented heart rate recovery to spontaneous cortical arousals may be an important mechanism contributing to the associations between insufficient sleep and cardiovascular risk

Morning sympathetic activity after evening binge alcohol consumption

Binge alcohol consumption elicits acute and robust increases of muscle sympathetic nerve activity (MSNA), yet the impact of evening binge drinking on morning-after MSNA is unknown. The present study examined the effects of evening binge alcohol consumption on polysomnographic sleep and morning-after MSNA. We hypothesized that evening binge drinking (i.e. 4-5 drink equivalent in \u3c2 \u3eh) would reduce sleep quality and increase morning-after blood pressure (BP) and MSNA. Following a familiarization night within the sleep laboratory, 22 participants (12 men, 10 women; 25 ± 1 yr) were examined after simulated binge drinking or fluid control (randomized, crossover design). Morning MSNA was successfully recorded across both conditions in 16 participants (8 men, 8 women) during a 10-min baseline and three Valsalva\u27s maneuvers (VM). Binge drinking reduced rapid eye movement (REM) sleep (15 ± 1 vs. 20 ± 1%, P = 0.003), increased stage II sleep (54 ± 1 vs. 51 ± 1%, P = 0.002), and increased total urine output (2.9 ± 0.2 vs. 2.1 ± 0.1 liters, P \u3c 0.001) but did not alter morning-after urine specific gravity. Binge drinking increased morning-after heart rate [65 (54-72) vs. 58 (51-67) beats/min, P = 0.013] but not resting BP or MSNA. Binge drinking elicited greater sympathoexcitation during VM (38 ± 3 vs. 43 ± 3 bursts/min, P = 0.036). Binge drinking augmented heart rate (P = 0.002), systolic BP (P = 0.022), and diastolic BP (P = 0.037) reactivity to VM phase IV and blunted cardiovagal baroreflex sensitivity during VM phases II (P = 0.028) and IV (P = 0.043). In conclusion, evening binge alcohol consumption disrupted REM sleep and morning-after autonomic function. These findings provide new mechanistic insight into the potential role of binge drinking on cardiovascular risk.NEW & NOTEWORTHY Chronic binge alcohol consumption is associated with future cardiovascular disease (CVD) risk in both men and women. In addition, binge alcohol consumption is known to disrupt normal sleep quality during the early morning hours, coinciding with the morning sympathetic surge. In the present study, an evening of binge alcohol consumption increased baseline morning heart rate and cardiovascular reactivity during the Valsalva maneuver (VM) strain. Specifically, muscle sympathetic nerve activity and phase IV hemodynamic responses increased during VM the morning after binge alcohol consumption. The autonomic dysfunction and increased cardiovascular reactivity during VM suggests a contributing mechanism to CVD risk present in individuals who binge drink

Morning Cardiovascular and Sympathetic Reactivity to Cold Pressor Test After Evening Binge Drinking: Sex Differences

Heavy alcohol consumption, including binge drinking, is associated with increased cardiovascular risk There is consistent evidence for increased muscle sympathetic nerve activity (MSNA) after acute alcohol consumption, and recent evidence for augmented sympathetic reactivity the morning after evening binge drinking. Given well documented differences in neural cardiovascular control between men and women, we hypothesized that women would exhibit augmented morning cardiovascular and sympathetic neural reactivity to cold stress following evening binge alcohol consumption. Thirty volunteers (15 women, 15 men; 25±1 years; 27±1 kg/m2 ) participated in the present study. Utilizing a randomized, cross-over design, participants visited the laboratory for fluid control and alcohol sessions separated by ~1 month. The alcohol dose was based upon biological sex and body weight (1 g/kg dose in men and 0.85 g/kg dose in women). Beverage consumption occurred at 8:00pm and 9:00pm to simulate binge alcohol consumption (i.e., 4-5 drink equivalent), with lights out at 11:00pm. An 8-hour sleep opportunity was allotted from 11:00pm to 7:00am for overnight polysomnography (NATUS, Middleton, WI). Following lights on, twenty-two (10 women, 12 men) participants were instrumented for a morning autonomic study with measurements of muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat blood pressure (finger plethysmography), and heart rate (electrocardiogram). MSNA, blood pressure, and heart rate were measured during a 3-minute baseline, 2-minute cold pressor test (CPT), and 3-minute recovery. MSNA was scored and confirmed by one trained investigator (JR Carter). Statistical analysis included repeated measures ANOVA with condition and time as within subject factors and sex as a between subject factor (α = 0.05). Total sleep time and sleep efficiency were reduced following binge alcohol consumption in both sexes (condition: p \u3c 0.05), but women had more frequent arousals following alcohol consumption (condition × sex: p = 0.008). During CPT, women exhibited an augmented pressor response via mean arterial pressure following evening binge alcohol consumption compared to fluid control, while men did not (condition × time × sex: p = 0.010). MSNA burst frequency was elevated during CPT following evening binge alcohol consumption compared to fluid control (condition × time: p = 0.033), but this was not different between sexes. Heart rate reactivity was not different across conditions (condition × time: p = 0.405) or between sexes (condition × time × sex: p = 0.818). In conclusion, our results indicate that evening binge drinking results in augmented cardiovascular reactivity in women compared to men, but these differences do not appear to be mediated via sympathetic neural reactivity