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• W3048647157 abstract "HomeHypertensionVol. 76, No. 3How Sympathetic Is Sympathetic Enough? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBHow Sympathetic Is Sympathetic Enough? Jens Jordan, Jens Tank Jens JordanJens Jordan Correspondence to Jens Jordan, Institute of Aerospace Medicine, Linder Hoehe, 51147 Cologne, Germany. Email E-mail Address: [email protected] https://orcid.org/0000-0003-4518-0706 From the Institute of Aerospace Medicine, German Aerospace Center (DLR) and University of Cologne, Germany. Search for more papers by this author , Jens TankJens Tank From the Institute of Aerospace Medicine, German Aerospace Center (DLR) and University of Cologne, Germany. Search for more papers by this author Originally published12 Aug 2020https://doi.org/10.1161/HYPERTENSIONAHA.120.15422Hypertension. 2020;76:672–674This article is a commentary on the followingInfluence of Sex and Age on Muscle Sympathetic Nerve Activity of Healthy Normotensive AdultsSee related article, pp 997–1005The article by Keir et al1 in this issue draws our attention to the sympathetic nervous system, which is crucial for human blood pressure regulation. Norepinephrine released from sympathetic efferent nerves regulates vascular tone, heart rate, cardiac contractility, renal sodium reabsorption, and renin release. Sympathetic cotransmitter release may modulate the response. Patients with degeneration of sympathetic efferent nerves or with genetic mutations rendering norepinephrine synthesis ineffective are unable to respond to hemodynamic challenges and suffer from disabling orthostatic hypotension. Conversely, excess sympathetic activity has been implicated in the pathogenesis of arterial hypertension, thus, providing a rational for interventional therapies targeting sympathetic cardiovascular control. Moreover, sympathetic activation can promote cardiovascular and renal damage. Animal models with isoproterenol-induced heart failure or patients with stress (takotsubo) cardiomyopathy are striking examples of rapidly evolving organ damage mediated through adrenergic overactivation. Finally, β-blockade, which mitigates sympathetic actions on the heart, improves cardiac remodeling and survival in patients following myocardial infarction or with heart failure and reduced left ventricular ejection fraction. Yet, when sympathetic activity is inhibited excessively, mortality may increase.2Over the last decades, multiple studies contributed knowledge on human physiology of cardiovascular sympathetic activity. Important regulatory mechanisms, such as the arterial baroreflex and peripheral chemoreceptors, have been delineated and are being translated to potential clinical applications. Research on hypertensive animal models led to the concept that renal denervation could have clinical utility. Furthermore, clinical conditions often associated with increased sympathetic activity have been identified, such as heart failure, obstructive sleep apnea, chronic obstructive pulmonary disease, resistant arterial hypertension, and preeclampsia among others. Finally, factors contributing to variability in sympathetic activity have been teased out, particularly sex and age. The latter could conceivably contribute to sex differences in cardiovascular risk and aging-associated disease.In this issue, Keir et al1 report data on muscle sympathetic nerve activity in 658 healthy persons with normal blood pressure. The analysis pooled sympathetic activity measurements obtained in 4 experienced laboratories. Methodologies to obtain and to analyze sympathetic measurements were harmonized between study sites. The pooled sample contained women and men over a wide age range, which together with the large sample size permitted detailed analyses of age and sex influences on sympathetic activity. The authors applied regression models to determine the interaction between gender, age, blood pressure, and muscle sympathetic nerve activity. Moreover, the authors assessed age-related trends using cubic splines. A similar approach is applied in engineering when constructing complex curved structures, such as train tracks or roller coasters.On average, sympathetic activity increased ≈3-fold when comparing younger participants with the oldest age group. At a younger age, sympathetic activity was lower in women compared with men. However, sympathetic activity at an age of ≈50 years the gender difference had disappeared similar to earlier observations.3 Remarkably, body mass index explained only a small portion of the variability of sympathetic activity in women and none in men. Possibly, visceral adipose tissue may be more important in that regard.4,5 Furthermore, while blood pressure increased with age and then tended to decrease, sympathetic activity and blood pressure were very weakly related to each other.The study by Keir et al1 is an important contribution to the literature assessing influences of aging and sex on sympathetic cardiovascular control confirming and extending earlier studies in smaller samples. Indeed, pharmacological studies suggested that the autonomic nervous system contributes less to blood pressure in premenopausal women than in men.6 However, aging-associated changes in autonomic blood pressure control are not solely explained by the sympathetic nervous system.7 More detailed knowledge on sex and age interactions on sympathetic activity could have clinical relevance. However, some of more hidden findings highlight important areas of uncertainty.We know little about the mechanisms that set sympathetic activity. The authors present a detailed list with normal ranges of sympathetic activity measurements in different age groups for women and for men. The information can now be used as a reference for future studies. Strikingly, in each age group, the interindividual variability in sympathetic activity is much greater than the variability contributed by either age or gender. Even when body mass index and blood pressure were considered, much of the interindividual variability in sympathetic activity was not explained. Studies on the interaction between adiposity and sympathetic activity suggest genetic contributions.8We do not know what constitutes excess sympathetic activity. The participants in the study by Keir et al1 were healthy and on no medications. Perhaps, the degree of sympathetic activation in each participant simply reflected the activity required to maintain normal blood pressure. Whether in the long-term lower or higher sympathetic activity would be beneficial or harmful in an otherwise healthy person is unknown. Perusal of previous studies conducted in resistant hypertension, metabolic syndrome, heart failure, and probably every other condition where sympathetic nerve activity has been measured shows that there is much overlap in sympathetic activity between patients and healthy persons of similar age. For example, the average muscle sympathetic nerve activity of 42 bursts/min in older patients with resistant arterial hypertension9 is well within the age-specific reference range defined by Keir et al.1 In the future, general statements that a condition is associated with sympathetic overactivity should be taken with caution. Indeed, such statements could promote overutilization of treatments targeting the sympathetic nervous system in patients unlikely to respond. In healthy persons, sympathetic activity at baseline determines blood pressure reductions elicited through pharmacological inhibition of the autonomic nervous system.7 Perhaps, individual physiological profiling could also be useful in patients considered for interventions modulating sympathetic nervous system activity.There is no gold standard for sympathetic activity measurements. Sympathetic cardiovascular control is complex and cannot be captured with a single methodology (Figure). The electrical activity of postganglionic sympathetic nerves, which is assessed through microneurography, elicits norepinephrine release. The released norepinephrine acts on postsynaptic receptor eliciting organ responses through intricate signaling mechanisms. On presynaptic adrenoreceptors, norepinephrine feeds back on further norepinephrine release. Released norepinephrine is taken up through neuronal norepinephrine transporters and either recycled or enzymatically degraded. Sympathetic efferent activity is modulated through spinal, brain stem, and higher brain areas making matters even more complicated. Moreover, sympathetic responses are affected by diurnal rhythms, activity, emotional state, and sleep among many others. Finally, influences of sympathetic activity on cardiovascular health may depend on the mechanisms driving the response which could be physical exercise in an athlete or hemodynamic compromise in heart failure patients. We should be cautious before reaching the verdict that sympathetic activity is too high in the patient in front of us.Download figureDownload PowerPointFigure. Cardiovascular sympathetic control mechanisms. Information generated in baroreceptors and peripheral chemoreceptors travels to the nucleus of the solitary tract (NTS). Barosensitive NTS neurons lead to sympathoinhibition via activation of interneurons in the caudal ventrolateral medulla (cVLM), which inhibit sympathetic premotor neurons in the rostral ventrolateral medulla (rVLM). rVLM neurons regulate preganglionic neurons located in the spinal intermediolateral column (IML) activating postganglionic sympathetic efferents traveling to vasculature, heart, and kidney. Muscle sympathetic nerve activity (MSNA) measures postganglionic sympathetic nerve fibers directed towards resistance vessels in the lower leg. Secretion of vasopressin, which also affects vascular tone, by hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei neurons is also regulated through barosensitive NTS neurons, in part through the A1 group of noradrenergic cells. Chemoreceptive cells located in the carotid bodies respond to changes in oxygen and carbon dioxide and are also connected via NTS neurons and cardiorespiratory medullary centers to the rVLM. Finally higher cortical centers modulate the nuclei in the hypothalamus and brain stem. Thus, MSNA covers only part of the mechanisms through which sympathetic mechanisms affect the cardiovascular system.In summary, too little and too much sympathetic activity can cause significant health problems. Thus, mechanisms regulating human sympathetic activity continue to deserve our attention. Advances in technology, such as brain stem imaging,10 may provide insight in human sympathetic control mechanisms that have not been accessible in the past. Clearly, new ways for individualized sympathetic assessment will be required to target therapies modulating sympathetic activity to patients likely to respond while avoiding that sympathetic activity is lowered too much.Sources of FundingNone.DisclosuresJ. Jordan served as a consultant for Novartis, Novo-Nordisk, Boehringer-Ingelheim, Sanofi, Theravance, Vivus and is cofounder of Eternygen GmbH. The other author reports no conflicts.FootnotesCorrespondence to Jens Jordan, Institute of Aerospace Medicine, Linder Hoehe, 51147 Cologne, Germany. Email jens.[email protected]deReferences1. Keir DA, Badrov MB, Tomlinson G, Notarius CF, Kimmerly DS, Millar PJ, Shoemaker JK, Floras JS. Influence of sex and age on muscle sympathetic nerve activity in healthy normotensive adults.Hypertension. 2020; 76:997–1005. 10.1161/HYPERTENSIONAHA.120.15208LinkGoogle Scholar2. Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, Wiltse C, Wright TJ; MOXCON Investigators. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON).Eur J Heart Fail. 2003; 5:659–667. doi: 10.1016/s1388-9842(03)00163-6CrossrefMedlineGoogle Scholar3. Narkiewicz K, Phillips BG, Kato M, Hering D, Bieniaszewski L, Somers VK. Gender-selective interaction between aging, blood pressure, and sympathetic nerve activity.Hypertension. 2005; 45:522–525. doi: 10.1161/01.HYP.0000160318.46725.46LinkGoogle Scholar4. Tank J, Heusser K, Diedrich A, Hering D, Luft FC, Busjahn A, Narkiewicz K, Jordan J. Influences of gender on the interaction between sympathetic nerve traffic and central adiposity.J Clin Endocrinol Metab. 2008; 93:4974–4978. doi: 10.1210/jc.2007-2820CrossrefMedlineGoogle Scholar5. Alvarez GE, Beske SD, Ballard TP, Davy KP. Sympathetic neural activation in visceral obesity.Circulation. 2002; 106:2533–2536. doi: 10.1161/01.cir.0000041244.79165.25LinkGoogle Scholar6. Christou DD, Jones PP, Jordan J, Diedrich A, Robertson D, Seals DR. Women have lower tonic autonomic support of arterial blood pressure and less effective baroreflex buffering than men.Circulation. 2005; 111:494–498. doi: 10.1161/01.CIR.0000153864.24034.A6LinkGoogle Scholar7. Jones PP, Shapiro LF, Keisling GA, Jordan J, Shannon JR, Quaife RA, Seals DR. Altered autonomic support of arterial blood pressure with age in healthy men.Circulation. 2001; 104:2424–2429. doi: 10.1161/hc4501.099308LinkGoogle Scholar8. Weyer C, Pratley RE, Snitker S, Spraul M, Ravussin E, Tataranni PA. Ethnic differences in insulinemia and sympathetic tone as links between obesity and blood pressure.Hypertension. 2000; 36:531–537. doi: 10.1161/01.hyp.36.4.531CrossrefMedlineGoogle Scholar9. Heusser K, Thöne A, Lipp A, Menne J, Beige J, Reuter H, Hoffmann F, Halbach M, Eckert S, Wallbach M, et al.. Efficacy of electrical baroreflex activation is independent of peripheral chemoreceptor modulation.Hypertension. 2020; 75:257–264. doi: 10.1161/HYPERTENSIONAHA.119.13925LinkGoogle Scholar10. Gerlach DA, Manuel J, Hoff A, Kronsbein H, Hoffmann F, Heusser K, Ehmke H, Diedrich A, Jordan J, Tank J, et al.. novel approach to elucidate human baroreflex regulation at the brainstem level: pharmacological testing during fMRI.Front Neurosci. 2019; 13:193. doi: 10.3389/fnins.2019.00193CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesInfluence of Sex and Age on Muscle Sympathetic Nerve Activity of Healthy Normotensive AdultsDaniel A. Keir, et al. Hypertension. 2020;76:997-1005 September 2020Vol 76, Issue 3Article InformationMetrics Download: 62 © 2020 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.120.15422PMID: 32783753 Originally publishedAugust 12, 2020 PDF download SubjectsAutonomic Nervous System" @default.
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