Is the Gut Microbiome Implicated in the Excess Risk of Hypertension Associated with Obstructive Sleep Apnea? A Contemporary Review

Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder and an established risk factor for cardiovascular diseases, including hypertension. The pathogenesis of elevated blood pressure (BP) in OSA is multifactorial, including sympathetic overdrive, vascular aberrations, oxidative stress, inflammation, and metabolic dysregulation. Among the mechanisms potentially involved in OSA-induced hypertension, the role of the gut microbiome is gaining increasing attention. Perturbations in the diversity, composition, and function of the gut microbiota have been causally linked to numerous disorders, and robust evidence has identified gut dysbiosis as a determinant of BP elevation in various populations. In this brief review, we summarize the current body of literature on the implications of altered gut microbiota for hypertension risk in OSA. Data from both preclinical models of OSA and patient populations are presented, and potential mechanistic pathways are highlighted, along with therapeutic considerations. Available evidence suggests that gut dysbiosis may promote the development of hypertension in OSA and may thus be a target for interventions aimed at attenuating the adverse consequences of OSA in relation to cardiovascular risk

Obesity, Body Composition, and Sex Hormones: Implications for Cardiovascular Risk

Cardiovascular disease (CVD) continues to be the leading cause of death in adults, highlighting the need to develop novel strategies to mitigate cardiovascular risk. The advancing obesity epidemic is now threatening the gains in CVD risk reduction brought about by contemporary pharmaceu-tical and surgical interventions. There are sex differences in the development and outcomes of CVD; premenopausal women have significantly lower CVD risk than men of the same age, but women lose this advantage as they transition to menopause, an observation suggesting potential role of sex hormones in determining CVD risk. Clear differences in obesity and regional fat distribution among men and women also exist. While men have relatively high fat in the abdominal area, women tend to distribute a larger proportion of their fat in the lower body. Considering that regional body fat distribution is an important CVD risk factor, differences in how men and women store their body fat may partly contribute to sex-based alterations in CVD risk as well. This article presents findings related to the role of obesity and sex hormones in determining CVD risk. Evidence for the role of sex hormones in determining body composition in men and women is also pre-sented. Lastly, the clinical potential for using sex hormones to alter body composition and reduce CVD risk is outlined. © 2022 American Physiological Society. Compr Physiol 12:2949-2993, 2022

Effects of Experimental Sleep Restriction on Ambulatory and Sleep Blood Pressure in Healthy Young Adults: A Randomized Crossover Study

Although insufficient sleep is associated with increased cardiovascular risk, evidence of a causal relationship is lacking. We investigated the effects of prolonged sleep restriction on 24-hour ambulatory blood pressure (BP) and other cardiovascular measures in 20 healthy young participants (aged 23.4±4.8 years, 9 females), who underwent a randomized, controlled, crossover, 16-day inpatient study consisting of 4 days of acclimation, 9 days of sleep restriction (4 hours of sleep/night) or control sleep (9 hours), and 3 days of recovery. Subjects consumed a weight maintenance diet with controlled nutrient composition throughout. A 24-hour BP (primary outcome) and cardiovascular biomarkers were measured repeatedly. Polysomnographic monitoring was continuous. Comparing sleep restriction versus control sleep, 24-hour mean BP was higher (adjusted mean difference, day 12: 2.1 mm Hg [95% CI, 0.6-3.6], corrected P=0.016), endothelial function was attenuated (P\u3c0.001), and plasma norepinephrine increased (P=0.011). Despite increased deep sleep, BP was elevated while asleep during sleep restriction and recovery. Post hoc analysis revealed that 24-hour BP, wakefulness, and sleep BP increased during experimental and recovery phases of sleep restriction only in women, in whom 24-hour and sleep systolic BP increased by 8.0 (5.1-10.8) and 11.3 (5.9-16.7) mm Hg, respectively (both P\u3c0.001). Shortened sleep causes persistent elevation in 24-hour and sleep-time BP. Pressor effects are evident despite closely controlled food intake and weight, suggesting that they are primarily driven by the shortened sleep duration. BP increases are especially striking and sustained in women, possibly suggesting lack of adaptation to sleep loss and thus greater vulnerability to its adverse cardiovascular effects

Effects of Experimental Sleep Restriction on Energy Intake, Energy Expenditure, and Visceral Obesity

Background: Although the consequences of sleep deficiency for obesity risk are increasingly apparent, experimental evidence is limited and there are no studies on body fat distribution. Objectives: The purpose of this study was to investigate the effects of experimentally-induced sleep curtailment in the setting of free access to food on energy intake, energy expenditure, and regional body composition. Methods: Twelve healthy, nonobese individuals (9 males, age range 19 to 39 years) completed a randomized, controlled, crossover, 21-day inpatient study comprising 4 days of acclimation, 14 days of experimental sleep restriction (4 hour sleep opportunity) or control sleep (9 hour sleep opportunity), and a 3-day recovery segment. Repeated measures of energy intake, energy expenditure, body weight, body composition, fat distribution and circulating biomarkers were acquired. Results: With sleep restriction vs control, participants consumed more calories (P = 0.015), increasing protein (P = 0.050) and fat intake (P = 0.046). Energy expenditure was unchanged (all P \u3e 0.16). Participants gained significantly more weight when exposed to experimental sleep restriction than during control sleep (P = 0.008). While changes in total body fat did not differ between conditions (P = 0.710), total abdominal fat increased only during sleep restriction (P = 0.011), with significant increases evident in both subcutaneous and visceral abdominal fat depots (P = 0.047 and P = 0.042, respectively). Conclusions: Sleep restriction combined with ad libitum food promotes excess energy intake without varying energy expenditure. Weight gain and particularly central accumulation of fat indicate that sleep loss predisposes to abdominal visceral obesity. (Sleep Restriction and Obesity; NCT01580761

Comparative Expression of Renin-Angiotensin Pathway Proteins in Visceral Versus Subcutaneous Fat

Body fat distribution contributes to obesity-related metabolic and cardiovascular disorders. Visceral fat is more detrimental than subcutaneous fat. However, the mechanisms underlying visceral fat-mediated cardiometabolic dysregulation are not completely understood. Localized increases in expression of the renin angiotensin system (RAS) in adipose tissue (AT) may be implicated. We therefore investigated mRNA and protein expression of RAS components in visceral versus subcutaneous AT using paired samples from individuals undergoing surgery (N = 20, body mass index: 45.6 ± 6.2 kg/m2, and age: 44.6 ± 9.1 years). We also examined RAS-related proteins in AT obtained from individuals on renin angiotensin aldosterone system (RAAS) targeted drugs (N = 10, body mass index: 47.2 ± 9.3 kg/m2, and age: 53.3 ± 10.1 years). Comparison of protein expression between subcutaneous and visceral AT samples showed an increase in renin (p = 0.004) and no change in angiotensinogen (p = 0.987) expression in visceral AT. Among proteins involved in angiotensin peptide generation, angiotensin converting enzyme (p = 0.02) was increased in subcutaneous AT while chymase (p = 0.001) and angiotensin converting enzyme-2 (p = 0.001) were elevated in visceral fat. Furthermore, visceral fat expression of angiotensin II type-2 receptor (p = 0.007) and angiotensin II type-1 receptor (p = 0.031) was higher, and MAS receptor (p < 0.001) was lower. Phosphorylated-p53 (p = 0.147), AT fibrosis (p = 0.138) and average adipocyte size (p = 0.846) were similar in the two depots. Nonetheless, visceral AT showed increased mRNA expression of inflammatory (TNFα, p < 0.001; IL-6, p = 0.001) and oxidative stress markers (NOX2, p = 0.038; NOX4, p < 0.001). Of note, mRNA and protein expression of RAS components did not differ between subjects taking or not taking RAAS related drugs. In summary, several RAS related proteins are differentially expressed in subcutaneous versus visceral AT. This differential expression may not alter AngII but likely increases Ang1-7 generation in visceral fat. These potential differences in active angiotensin peptides and receptor expression in the two depots suggest that localized RAS may not be involved in differences in visceral vs subcutaneous AT function in obese individuals. Our findings do not support a role for localized RAS differences in visceral fat-mediated development of cardiovascular and metabolic pathology

Sex-specific associations between daytime sleepiness, chronic diseases and mortality in obstructive sleep apnea

ObjectiveExcessive daytime sleepiness (EDS) is common in obstructive sleep apnea (OSA) and has been linked to adverse outcomes, albeit inconsistently. Furthermore, whether the prognostic impact of EDS differs as a function of sex is unclear. We aimed to assess the associations between EDS and chronic diseases and mortality in men and women with OSA.MethodsNewly-diagnosed adult OSA patients who underwent sleep evaluation at Mayo Clinic between November 2009 and April 2017 and completed the Epworth Sleepiness Scale (ESS) for assessment of perceived sleepiness (N = 14,823) were included. Multivariable-adjusted regression models were used to investigate the relationships between sleepiness, with ESS modeled as a binary (ESS > 10) and as a continuous variable, and chronic diseases and all-cause mortality.ResultsIn cross-sectional analysis, ESS > 10 was independently associated with lower risk of hypertension in male OSA patients (odds ratio [OR], 95% confidence interval [CI]: 0.76, 0.69–0.83) and with higher risk of diabetes mellitus in both OSA men (OR, 1.17, 95% CI 1.05–1.31) and women (OR 1.26, 95% CI 1.10–1.45). Sex-specific curvilinear relations between ESS score and depression and cancer were noted. After a median 6.2 (4.5–8.1) years of follow-up, the hazard ratio for all-cause death in OSA women with ESS > 10 compared to those with ESS ≤ 10 was 1.24 (95% CI 1.05–1.47), after adjusting for demographics, sleep characteristics and comorbidities at baseline. In men, sleepiness was not associated with mortality.ConclusionThe implications of EDS for morbidity and mortality risk in OSA are sex-dependent, with hypersomnolence being independently associated with greater vulnerability to premature death only in female patients. Efforts to mitigate mortality risk and restore daytime vigilance in women with OSA should be prioritized

Hemodynamic and autonomic patterns during sleep in essential hypotension

Over the past decade, a large body of knowledge has been gathered with regard to the nocturnal hemodynamic pattern, as well as the comorbidity with sleep disturbances, in several cardiovascular diseases, such as hypertension. Nevertheless, surprisingly few attention has been paid to the hypotensives states. In particular, there is paucity of studies addressing sleep in essential hypotension. Essential hypotension represents a form of chronic low blood pressure that is not due to medical or orthostatic conditions. Unlike the other forms of hypotension and although sufferers endorse a variety of subjective distressing symptoms included sleep complaints, essential hypotension remains a poorly addressed topic. Considering in particular its pathogenesis, an autonomic dysfunction in terms of a sympathetic hypoactivation has been postulated as underlying this condition. The present dissertation aims at providing a comprehensive picture of the hemodynamic and autonomic pattern during sleep as well as the sleep pattern in essential hypotension in comparison to normotensive state. The aim of the Experiment 1 was to survey the overnight profile of cardiovascular activity during a night of sleep in essential hypotensives by means of a wide range of measures derived from blood pressure monitoring, impedance cardiography and heart rate variability. In addition, in order to clarify the postulated autonomic imbalance in hypotensives, we sought to examine the nocturnal cardiac autonomic regulation by assessing the involvement of both neurovegetative divisions. Hypotensives displayed diminished cardiovascular output over the sleep period in comparison to normotensives, which was likely driven by the finding of both sympathetic hypoactivation and vagal hyperactivity in essential hypotension. Afterwards, the focus has been turned on the sleep structure. The purpose of the Experiment II was twofold. Firstly, we aimed at evaluating the sleep quality and quantity in this condition in depth, by describing the sleep parameters through polysomnographic recording. Secondly, we studied the cardiovascular and autonomic patterns as a function of the sleep stage to assess whether hypotensives have a different regulation across sleep stages compared with normotensives. Comparisons over the sleep parameters failed to identify any group differences in sleep pattern, whereas lower blood pressure and myocardial contractility associated with a decreased sympathovagal balance in hypotensives across sleep stages corroborated the nighttime cardiovascular hypoactivation and autonomic dysregulation illustrated in the Experiment I. Lastly, since arousals from sleep are associated with transient elevations in cardiovascular activity, the analysis of changes in heart rate elicited by arousals from sleep was carried out in the Experiment III to assess the cardiovascular reactivity in essential hypotension. Hypotensive individuals exhibited a larger heart rate response over the early post arousal beats compared to normotensives, whilst groups did not differ in terms of neither the number nor the duration of arousals experienced during sleep. Given that the cardiac arousal response is primarily mediated by the parasympathetic division, this finding suggests a greater vagal withdrawal in hypotensive subjects than in normotensives, providing further support to the hypothesized parasympathetic hyperactivity in essential hypotension. To summarize, our findings of sympathetic withdrawal matched with vagal hyperactivity underlying the nocturnal cardiovascular activity confirm and extend the hypothesis of autonomic imbalance in essential hypotension, showing that both neurovegetative branches functions are altered in this condition. Nevertheless, since no group differences were detected with regard to the objective sleep parameters, the sleep quality and quantity appear to be preserved in this disorder.A partire dallo scorso decennio, è stata ampiamente approfondita la conoscenza relativa all’andamento dei parametri cardiovascolari durante la notte, così come la comorbidità con disturbi del sonno, in numerose patologie cardiovascolari quale l’ipertensione arteriosa. Tuttavia, sorprendentemente limitata attenzione è stata prestata agli stati ipotensivi. In particolare, scarseggiano gli studi volti ad esaminare il sonno nell’ipotensione essenziale. L’ipotensione essenziale rappresenta una forma cronica di bassa pressione sanguigna non conseguente a condizioni mediche o ortostatiche. A differenza delle altre forme di ipotensione e nonostante i soggetti che ne soffrono lamentino una varietà di sintomi soggettivi inclusi difficoltà nel sonno, l’ipotensione essenziale rimane un tema insufficientemente indagato. Considerando in particolare la patogenesi, una disfunzione autonoma in termini di ipoattivazione simpatica è stata ipotizzata alla base di tale condizione. La presente tesi si propone di fornire una descrizione esaustiva dell’andamento emodinamico e autonomo durante il sonno e del pattern ipnico nell’ipotensione essenziale in confronto con lo stato normotensivo. L’obiettivo dell’Esperimento I era quello di indagare il profilo notturno dell’attività cardiovascolare durante una notte di sonno in ipotési essenziali mediante l’impiego di un ampio spettro di misure derivate dal monitoraggio pressorio, dalla cardiografia ad impedenza e dall’analisi della variabilità della frequenza cardiaca. Inoltre, al fine di chiarire l’ipotesi di sbilancio autonomo avanzata circa la patogenesi dell’ipotensione essenziale, abbiamo esaminato la regolazione cardiaca autonoma notturna valutando il ruolo di entrambe le divisioni neurovegetative. Gli ipotési, confrontati con normotesi, hanno mostrato una ridotta attività cardiovascolare lungo il periodo di sonno, verosimilmente mediata dalle ipoattivazione simpatica e iperattivazione vagale riscontrate nell’ipotensione essenziale. Il focus è stato quindi rivolto alla struttura del sonno. L’Esperimento II presentava un duplice scopo. In primo luogo, ci siamo proposti di esaminare approfonditamente la qualità e quantità di sonno nella condizione ipotensiva, attraverso la descrizione dei parametri sonno derivati dalla registrazione polisonnografica. In secondo luogo, abbiamo studiato i pattern cardiovascolare e autonomo in funzione dello stadio di sonno al fine di valutare se gli ipotési, confrontati con normotesi, mostrassero una differente regolazione fisiologica lungo tali stadi. I confronti effettuati circa i parametri sonno non hanno rilevato alcuna differenza di gruppo nel pattern ipnico, mentre i risultati di ridotte pressione sanguigna e contrattilità miocardica, unitamente ad un diminuito bilancio simpatovagale esibiti dagli ipotési lungo gli stadi di sonno hanno fornito supporto ai dati di ipoattivazione cardiovascolare notturna e disregolazione autonoma precedentemente illustrate nell’Esperimento I. Infine, dal momento che gli arousal notturni sono associati a transitori incrementi nei parametri cardiovascolari, nell’Esperimento III è stata condotta l’analisi delle variazioni di frequenza cardiaca elicitate dagli arousal notturni per indagare la reattività cardiovascolare nell’ipotensione essenziale. I soggetti ipotési hanno esibito una più marcata risposta cardiaca rispetto ai normotesi a livello dei battiti cardiaci immediatamente successivi all’insorgenza dell’arousal, mentre non si sono riscontrate differenze di gruppo relativamente né al numero né alla durata media degli arousal esperiti durante il sonno. Poiché la risposta cardiaca agli arousal è prevalentemente modulata dalla divisione parasimpatica, questo risultato suggerisce un maggiore ritiro vagale negli ipotési in confronto con i normotesi, avvalorando così ulteriormente l’ipotesi di iperattività vagale sottesa all’ipotensione essenziale. In conclusione, i risultati da noi riportati indicanti un ritiro simpatico congiuntamente ad un’iperattività vagale alla base dell’attività cardiovascolare notturna sostengono ed ampliano l’ipotesi di sbilancio autonomo postulata nell’ipotensione essenziale, suggerendo come entrambe le branche neurovegetative evidenzino alterazioni funzionali in tale condizione. Tuttavia, dal momento che non si sono rilevate differenze di gruppo circa i parametri sonno oggettivi, la qualità e quantità di sonno appaiono preservate in questo disturbo

The cardiovascular system during sleep

The majority of molecular, physiological, and behavioural processes undergo substantial variations across a 24 h period. The health implications of such fluctuations, whether they are expressions of an intrinsic circadian rhythmicity or are secondary to changes in physical activity, posture, and/or sleep, are increasingly recognized. Similar to other biological functions, the cardiovascular system exhibits a prominent day–night profile, with profound haemodynamic, autonomic, and hormonal oscillations occurring during the sleep period. These time-dependent and sleep stage-dependent patterns of function have important clinical significance. The cardiovascular downregulation achieved throughout the night while asleep may be restorative and protective against adverse events, while the morning physiological activation coincident with awakening facilitates resumption of daytime activities. Nevertheless, rather than beneficial, these activity configurations may be pathogenic in individuals with a vulnerable substrate and may favour onset and progression of cardiovascular diseases. Cardiovascular complications may also arise as a consequence of abnormal day–night periodicity and disturbed sleep quantity and quality. Hence, consideration of the diurnal pattern of cardiovascular activity is critical in the clinical setting.</p