Sleepless in Seattle: Sleep Deprivation and Fragmentation Impair Endothelial Function and Fibrinolysis in Hypertension

HomeHypertensionVol. 78, No. 6Sleepless in Seattle: Sleep Deprivation and Fragmentation Impair Endothelial Function and Fibrinolysis in Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBSleepless in Seattle: Sleep Deprivation and Fragmentation Impair Endothelial Function and Fibrinolysis in Hypertension Thomas Münzel, Omar Hahad and Andreas Daiber Thomas MünzelThomas Münzel Correspondence to: Thomas Münzel, Department for Cardiology 1, University Medical Center Mainz, Geb. 605, Langenbeckstr. 1, 55131 Mainz, Germany. Email E-mail Address: [email protected] https://orcid.org/0000-0001-5503-4150 Department for Cardiology 1, University Medical Center Mainz, Germany. German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany. Search for more papers by this author , Omar HahadOmar Hahad Department for Cardiology 1, University Medical Center Mainz, Germany. German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany. Search for more papers by this author and Andreas DaiberAndreas Daiber https://orcid.org/0000-0002-2769-0094 Department for Cardiology 1, University Medical Center Mainz, Germany. German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany. Search for more papers by this author Originally published10 Nov 2021https://doi.org/10.1161/HYPERTENSIONAHA.121.18196Hypertension. 2021;78:1841–1843This article is a commentary on the followingNegative Influence of Insufficient Sleep on Endothelial Vasodilator and Fibrinolytic Function in Hypertensive AdultsSee related article, pp 1829–1840With their present work, Stockelman et al1 demonstrate that insufficient sleep may worsen endothelial dysfunction and the impairment of fibrinolytic function in hypertensive adults, all of which was normalized by vitamin C infusion indicating a causative role of oxidative stress for impaired endothelial function induced by reduced sleep quality. High blood pressure is considered as one or even the leading health risk factor as revealed by data from the Global Burden of Disease Study.2 Hypertension and other cardiovascular sequela such as ischemic heart disease and cerebrovascular disease account together for >50% of premature mortality of the world population and almost a quarter of healthy life years lost due to living with severe illness and disability.2 Importantly, endothelial dysfunction is not only an established early prognostic marker of subclinical atherosclerosis3 but also strongly associated with arterial hypertension4 that was corrected by vitamin C infusion suggesting a central role of oxidative stress in endothelial dysfunction of hypertensive subjects.5 Importantly, chronic sleep deprivation has previously demonstrated to worsen endothelial function as assessed by flow-mediated dilation in healthy male young adults.6 The mechanisms of endothelial dysfunction are likely multifactorial but mostly associated with a reduced vascular nitric oxide (·NO) bioavailability due to oxidative degradation of the ·NO molecule by superoxide (O2.−) to form the highly reactive intermediate peroxynitrite, which in turn may uncouple the eNOS (endothelial nitric oxide synthase) and inhibit the soluble guanylyl cyclase.7,8With the present studies, Stockelman et al1 report an attenuated acetylcholine-dependent forearm blood flow in hypertensive adults with insufficient sleep (<7 h/night) as measured by venous occlusion plethysmography (Figure).1 In contrast, bradykinin-dependent responses were not different between subjects with short and normal sleep duration, which is somewhat puzzling as both agonists, acetylcholine and bradykinin cause vasodilation via G-protein–coupled receptor-mediated increase in intracellular calcium levels representing a strong stimulus for eNOS.Download figureDownload PowerPointFigure. Impact of insufficient sleep on endothelial function and fibrinolytic function in hypertensive adults.1 Sleep deprivation causes endothelial dysfunction as measured by acetylcholine (ACh)-induced forearm blood flow using venous occlusion plethysmography, which is corrected by infusion of the antioxidant vitamin C. Short sleep also impairs fibrinolysis based on endothelial tPA (tissue-type plasminogen activator) release upon bradykinin stimulation. Thereby, cardiovascular and hemostatic dysregulation by insufficient sleep shares similar pathomechanisms as those caused by nocturnal noise exposure. Image for forearm plethysmography was taken from Daiber et al3 with permission. Copyright ©2016, The British Pharmacological Society.Although the authors explain that bradykinin has an endothelial membrane hyperpolarizing component besides eNOS activation, numerous studies in the past have shown that endothelial dysfunction can be assessed by bradykinin-based plethysmography, for example, in normotensive versus hypertensive individuals (eg, Taddei et al9).As expected, insufficient sleep did not affect endothelium-independent vasodilation as determined by sodium nitroprusside infusion. The inactivation of eNOS-dependent ·NO formation by short sleep is well documented by the lack of effect of the NOS inhibitor L-NG-monomethyl arginine, which in contrast causes a severe reduction of acetylcholine-induced forearm blood flow in the normal sleep group. A role of oxidative stress for endothelial dysfunction in the short sleep group is demonstrated by a significant improvement of acetylcholine-induced forearm blood flow by vitamin C infusion that is absent in the group with normal sleep.The fibrinolytic function of the endothelium in response to bradykinin is measured by tPA (tissue-type plasminogen activator) release, a serine protease that catalyzes the conversion of plasminogen to plasmin (Figure).1 The latter is a potent suppressor of blood clotting, thus preventing thrombus formation. Importantly, endothelial tPA release to bradykinin was significantly lower (≈25%) in the short versus normal sleep duration adults. Coinfusion of vitamin C induced greater tPA release in short sleepers. Taken together, in hypertensive adults, Stockelman et al1 demonstrate that insufficient sleep is associated with reduced nitric oxide-mediated endothelium-dependent vasodilation and endothelial tPA release. These sleep-related abnormalities in endothelial function are due, in part, to oxidative stress.Several questions, however, remain. The understanding of the presented data could be improved if the authors would have not only used a complex equation of net tPA activity by also including the PAI-1 (plasminogen activator inhibitor-1) antigen but rather also separate data for each parameter. However, tPA activity allows the discrimination between net release/uptake and thereby represents an important readout of endothelial defense capacity against excessive fibrin deposition and thrombosis as discussed in detail by Stockelman et al.1 In addition, other markers of enhanced platelet activity and blood coagulation factors in the intrinsic and extrinsic pathway such as levels of fibrinogen, fibrin, tissue factor and thrombin (eventually also FX, FXI, FXII, and others) or even functional read-out based on activated partial thromboplastin time and prothrombin time/international normalized ratio (also known as the quick value) would have been of great interest for a more complete insight into mechanisms on thrombotic risk in response to sleep deprivation.Sleep deprivation or fragmentation is a well-known cardiovascular risk factor is acknowledged as a central player in nighttime noise-induced cardiovascular disease.10,11 Traffic noise causes an annual loss of 903 000 healthy life years for sleep disturbance and 654 000 for annoyance in Europe.10 As shown by Rudzik et al,12 nighttime noise exposure decreases amplitudes of sleep spindles that are highly protective and important for memory consolidation. Large population studies also suggest that noise exposure during the early (shortly after falling asleep) or late phase (preceding the daily awakening time) of sleep is most annoying and therefore most detrimental.10 We have also conducted several clinical field studies demonstrating that aircraft noise and train noise exposure for only one night triggers endothelial dysfunction (measured by flow-mediated dilation), increased blood pressure, impaired sleep quality, and cardiac diastolic function, caused sympathovagal imbalance and increased stress hormone release as well as proatherothrombotic phenotypic change of the plasma proteome in healthy subjects.10,11 Noise-induced endothelial dysfunction was partly normalized by vitamin C intake.10,11 Babisch et al showed with the Speedwell study that platelet count, plasma viscosity and blood pressure are even increased by noise exposure during the early morning and night (between 6 am and 10 pm).11Noise exposure of mice during their sleeping phase causes more pronounced adverse cardiovascular and also cerebral health side effects as compared to noise exposure during their awake phase.11 In noise-exposed mice, a large number of genes regulating and constituting the circadian clock system (eg, cryptochrome and period) were dysregulated pointing towards phase shifts and altered amplitudes. The impaired circadian gene expression was associated with enhanced neuronal activation and stress responses, neuroinflammation, and cerebral oxidative stress, ultimately leading to vascular oxidative stress and inflammation, endothelial dysfunction, and higher blood pressure. Of note, we also observed downregulated and uncoupled neuronal nitric oxide synthase in brains of around-the-clock noise-exposed mice, which may partly explain the impairment of cognition and memory capacity in children exposed to high levels of noise.10,11 These preclinical findings are well supported by previous reports on induction of vascular and cerebral oxidative stress by severe life stress, including sleep deprivation, followed by vascular and neuronal inflammation and activation of the angiotensin-II pathway, leading to an activation of the NADPH oxidase (mainly NOX-2).13In summary, the work by Stockelman et al1 provides important new mechanistic insight explaining at least in part the increased cardiovascular risk caused by sleep deprivation in shift workers. Importantly, the authors identify the induction of oxidative stress, endothelial dysfunction, and impaired fibrinolytic activity as major pathomechanisms triggered by insufficient sleep (Figure). These observations offer new pharmacological (eg, potentially eNOS enhancers/activators or soluble guanylyl cyclase activators/stimulators) or nonpharmacological approaches (eg, potentially physical exercise or intermittent fasting) to prevent the adverse cardiovascular effects of sleep disturbances. Of note, insufficient sleep shares similar pathomechanisms as those caused by nocturnal noise-induced impairment of sleep quality and subsequent, oxidative stress, inflammation, endothelial dysfunction, and hypertension. In the case of noise-induced cardiovascular complications the pathomechanisms are downstream of neuronal stress responses via activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system.Article InformationAcknowledgmentsThe expert graphical assistance by Margot Neuser is gratefully acknowledged. We acknowledge the continuous support by the Foundation Heart of Mainz and the DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany. Thomas Münzel is PI of the DZHK Rhein-Main.DisclosuresNone.FootnotesFor Disclosures, see page 1843.Correspondence to: Thomas Münzel, Department for Cardiology 1, University Medical Center Mainz, Geb. 605, Langenbeckstr. 1, 55131 Mainz, Germany. Email [email protected]deReferences1. Stockelman KA, Bain AR, Goulding A, DeSouza NM, Rahaman C, Maly L, Greiner JJ, Stauffer BL, DeSouza CA. Negative influence of insufficient sleep on endothelial vasodilator and fibrinolytic function in hypertensive adults.Hypertension. 2021; 78:1829–1840. doi: 10.1161/HYPERTENSIONAHA.121.17781LinkGoogle Scholar2. Murray CJ, Ezzati M, Flaxman AD, Lim S, Lozano R, Michaud C, Naghavi M, Salomon JA, Shibuya K, Vos T, et al.. 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