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

Sleep Apnea, Hypertension and the Sympathetic Nervous System in the Adult Population

Sleep apnea is very common in patients with cardiovascular disease, especially in patients with hypertension. Over the last few decades a number of discoveries have helped support a causal relationship between the two and even resistant hypertension. The role neurogenic mechanisms play has gathered more attention in the recent past due to their immediate bedside utility. Several innovative discoveries in pathogenesis including those exploring the role of baroreflex gain, cardiovascular variability, chemoreceptor reflex activation and the sympathetic nervous system have emerged. In this review, we discuss the epidemiology of sleep apnea and hypertension and the pathogenic mechanisms contributing to neurogenic hypertension. Furthermore, recent management strategies in addition to continuous positive airway pressure (CPAP), such as upper airway stimulation and renal denervation that target these pathogenic mechanisms, are also discussed

Relationship between cardiovascular resting state and visual attention

Introduction: Cardiovascular features seem to modulate performance in attention tasks. Methods: We investigated the relationship between blood pressure, resting heart rate and heart rate variability (HRV) and performance in a visuospatial attention task comparing normotensive and hypotensive young adults. Conclusions: We found an association between resting HRV and visual attention performance only in the normotensive group. In addition, we provided a further evidence of attention impairment in hypotensive individuals

Cardiac autonomic profile during rest and working memory load in essential hypotensive women

To our knowledge, no previous study has provided reliable data supporting a different modulation of the Neurovegetative system in essential hypotension. Our purpose was to provide, in essential hypotensive women compared to normotensives, evidence of a distinct sympathetic and parasympathetic cardiac control. Cardiovascular and autonomic indexes derived by impedance cardiography (heart rate, HR; pre-ejection period, PEP), photoplethysmographic technique (blood pressure, BP) and heart rate variability analysis (high and low frequencies power, HF and LF) were continuously collected during rest and mental stress condition. Hypotensives, compared to normotensives, exhibited prolonged PEP (low sympathetic tone) and elevated HF (high vagal involvement) during rest. In addition, they showed cardiovascular (reduced increases in BP and HR) and sympathetic (lower reductions of PEP) hypo-reactivity to the task. Furthermore, a lower sympathetic reactivity in hypotensiveswas associated to a poorer task performance. Essential hypotensionwas characterized by a low sympathetic and high parasympathetic tone. In addition, a reduced sympathetic nervous system reactivity suggests the main role of the Neurovegetative system in mediating the relationship between blood pressure and cognitive performance in hypotensives

Working memory impairment and cardiovascular hyperarousal in young primary insomniacs

We investigated memory performance and cardiovascular activity in 13 primary insomniacs (PI) compared to 13 good sleepers (GS). Cardiovascular and hemodynamic measures, including heart rate, pre-ejection period, and blood pressure, were continuously recorded at rest and during two memory tasks. PI showed working memory impairment under high cognitive load, but performed as well as GS in an easy memory task. In addition, PI exhibited markers of hyperarousal both at rest and during the execution of the two tasks. However, we failed to find a clear-cut relationship between cardiovascular hyperarousal and cognitive performance in insomniacs. Our data provide further evidence of both cognitive impairment and cardiovascular hyperarousal in primary insomnia, while not supporting the hypothesis of hyperarousal as a compensatory mechanism to overcome cognitive challenges

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