Extracting Information From Sympathetic Nerve Traffic in Gestational Hypertension.

HomeHypertensionVol. 80, No. 2Extracting Information From Sympathetic Nerve Traffic in Gestational Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBExtracting Information From Sympathetic Nerve Traffic in Gestational Hypertension Sarah L. Walton and Kate M. Denton Sarah L. WaltonSarah L. Walton https://orcid.org/0000-0002-8099-0272 Monash Biomedicine Discovery Institute (S.L.W., K.M.D.), Monash University, Clayton, Victoria, Australia. Department of Physiology (S.L.W., K.M.D.), Monash University, Clayton, Victoria, Australia. Search for more papers by this author and Kate M. DentonKate M. Denton Correspondence to: Kate M Denton, 26 Innovation Walk, Clayton, Monash University, VIC Australia 3800. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5929-4387 Monash Biomedicine Discovery Institute (S.L.W., K.M.D.), Monash University, Clayton, Victoria, Australia. Department of Physiology (S.L.W., K.M.D.), Monash University, Clayton, Victoria, Australia. Search for more papers by this author Originally published18 Jan 2023https://doi.org/10.1161/HYPERTENSIONAHA.122.20181Hypertension. 2023;80:302–304This article is a commentary on the followingSympathetic Action Potential Firing and Recruitment Patterns Are Abnormal in Gestational HypertensionSee related article, pp 291–301Hypertensive disorders of pregnancy are a complex spectrum of diseases encompassing gestational hypertension, chronic hypertension, preeclampsia, and superimposed preeclampsia. Up to 15% of all pregnancies are affected, of which gestational hypertension and preeclampsia are the most common.1 Combined, hypertensive pregnancy disorders are the global leader of maternal and fetal morbidity and mortality.1 These disorders have a wide and varying cause, and the mechanisms contributing to their pathogenesis are unclear. This makes identifying patients at risk and developing appropriate treatments challenging, despite the urgent need to do so. Known for decades, a common feature of hypertensive pregnancy disorders is aberrant cardiovascular adaptations in response to pregnancy. This can manifest as widespread endothelial dysfunction, renal impairment, and abnormal placentation, all contributing to maternal disease and impaired fetal development.1 Many of the adaptations to normal pregnancy are mediated in part by actions of the autonomic nervous system, and sympathetic overactivity underlies many cardiovascular diseases in nonpregnant populations.2 Therefore, it is reasonable to hypothesize that sympathetic overactivity also contributes to pregnancy-associated hypertensive disorders.2,3 Yet, evidence for the role of sympathy overactivity in gestational hypertension across a handful of studies is equivocal.In the current issue of Hypertension, Badrov et al3 advance our understanding of the pathophysiology underlying gestational hypertension (Figure). In a cross-sectional study, the authors examined whether gestational hypertension is associated with aberrant sympathetic action potential firing and neural recruitment strategies. Pregnant women were recruited into three cohorts: low-risk normotensive pregnancies, high-risk normotensive pregnancies, and gestational hypertension developed in late pregnancy. Using microneurography on the peroneal nerve, muscle sympathetic nerve activity (MSNA) at rest (supine) and in response to postural stress (head-up tilt) was measured in these women at late pregnancy (32–36 weeks of gestation) and compared to a cohort of healthy, nonpregnant women (Figure). The traditional microneurographic approach to measure MSNA consolidates neural activity information from a nerve bundle.4 As a result, MSNA provides information regarding sympathetic outflow to the skeletal muscle but all information related to individual actional potentials is masked. To gain greater resolution, the authors employed their unique wavelet-based technique4 to extract individual sympathetic action potentials from raw MSNA signals, which were subsequently classified into bins. At rest, high total action potential firing frequency was detected in women with gestational hypertension versus women in the low- and high-risk normotensive pregnancy groups. Thus, the authors confirmed several previous reports5,6 demonstrating a direct association between sympathetic overactivity and blood pressure in pregnancy. For example, the group have previously shown augmented MSNA in gestational hypertension is established in early pregnancy, before the onset of overt disease.7 The novelty of the article at hand lies within the MSNA response to orthostatic stress. Intriguingly, blunted (and almost absent) head-up tilt responses in women with gestational hypertension were detected. The authors speculate this may reflect a ceiling-like effect, where augmented sympathetic activity at rest reduces the residual capacity to respond to postural stress. The underlying cause of this is unknown but appears to reflect a fundamental difference in neural coding of autonomic control of cardiovascular reflexes in women who develop gestational hypertension. Interestingly, reports suggest augmented MSNA is not a feature of preeclampsia,5,8 meaning enhanced neurovascular transduction may distinguish gestational hypertension from preeclampsia.Download figureDownload PowerPointFigure. Badrov et al3 identified gestational hypertension is associated with aberrant sympathetic activity at rest and in response to postural stress. The authors used a niche filtering technique to extract individual action potential information from multiunit muscle sympathetic nerve activity (MSNA) recordings via microneurography of the peroneal nerve. These results suggest sympatho-inhibitory pathways are a suitable target for women with gestational hypertension to prevent or limit adverse maternal and fetal outcomes. Created with BioRender.com. BP indicates blood pressure; and HR, heart rate.There is urgent need for evidence-based therapies and treatment strategies for women with hypertensive disorders of pregnancy. This is challenging given there is no “universal” contributor to hypertensive pregnancy disorders, and pharmacotherapies may elicit fetal teratogenic effects. Therefore, tailored treatments for individuals are the way forward, and this study may help to identify women at risk of developing gestational hypertension specifically. For example, an individualized treatment program taking into account exaggerated resting sympathetic activity may benefit this population and is feasible given many of the current treatments for pregnancy-induced hypertension have neuromodulatory effects.1 Preventing or limiting effects in the mother will directly confer benefits to the developing fetus, given the unequivocal evidence that gestational hypertension predisposes offspring to cardiovascular diseases later in life.1,9Delineating the complex mechanistic pathways that contribute to gestational hypertension requires the use of preclinical models. One such example already in use is the reduced uterine perfusion pressure model of pregnancy-induced hypertension in the rat, in which enhanced sympathetic nerve activity supports the involvement of the sympathetic nervous system in preeclampsia.10 Similar models of gestational hypertension will facilitate direct assessment of whether sympathetic overactivity initiates disease, or is simply implicated in disease progression, for example arising following endothelial dysfunction and aberrant activity of the renin-angiotensin aldosterone system. Mechanisms of interest that modulate sympathetic nerve activity include but are not limited to, the renin-angiotensin aldosterone system, inflammation, and neurohormonal factors. Furthermore, testing novel sympatho-inhibitory compounds in preclinical models will directly tackle the lack of effective therapies to treat hypertensive pregnancy disorders in women.The main strength of the study by Badrov et al3 is the exploration of sympathetic activity to the level of individual action potentials. The multiunit detection technique has allowed the authors to measure recruitment of latent neural populations, which cannot be directly addressed with single-unit measurements. Furthermore, comparisons to the healthy, nonpregnant cohort of women provide useful information regarding normal pregnancy physiology. There are limitations to the present study to consider. It is possible differential hemodynamic responses in high-risk/gestational hypertensive pregnancies to the head tilt stressor may alter interpretation of the neural recruitment response. Incorporating stress tests that exclude hemodynamic shifts, such as isometric handgrip exercise, into future study designs may address this issue. The sample size is limited, precluding demographic stratification by age and ethnicity, although we state this in full acknowledgment that this is a challenging patient population pool to recruit from.Future studies should endeavor to combine MSNA measurements as described in the present study, which are currently limited to experimental settings, with noninvasive biochemical correlates of sympathetic nerve activity. One example is corin, an atrial natriuretic peptide-converting enzyme expressed in the heart, which the authors previously reported directly correlates with resting blood pressure at late pregnancy and MSNA at early and late pregnancy.7 Biomarkers suitable for serial assessments in pregnant women, such as corin,7 will promote translation to the clinic. There is need to extend beyond cross-sectional study design towards longitudinal cohort studies to address whether the phenotype is unmasked by pregnancy, or whether the gestational hypertension directly augments sympathetic action potential firing and recruitment. We should also seek to understand the longitudinal relationship between aberrant gestational sympathetic nerve activity and postpartum cardiovascular disease, which is increasingly highlighted as an emerging field of interest.1 For example, does aberrant sympathetic activity resolve postpartum, and if not, does this confer increased risk of cardiovascular dysfunction? This is of great importance when we consider the concerning and overlooked statistics that hypertensive pregnancy disorders increase risk of postpartum cardiovascular disease significantly.1,2In summary, the findings of Badrov and colleagues3 further highlight the need for more precise mechanistic understanding of hypertensive pregnancy disorders. Alterations detected in neurovascular transduction suggest a mechanism for the pathogenesis of gestational hypertension. Therefore, sympathetic nerve activity represents an important opportunity for treatment of gestational hypertension in this understudied population of women. There is still a great deal to learn about the sympathetic nervous system and its contribution to blood pressure elevation in hypertensive disorders of pregnancy. Use of the authors’ niche technique to filter and extract action potential information from raw MSNA measurements contributes to our understanding of the pathogenesis of other hypertensive disorders of pregnancy and waits to be applied to other pathologies where disturbances in sympathetic activity are implicated. These are important questions to address to improve the poor maternal and fetal outcomes currently associated with hypertensive pregnancy disorders.Article InformationSources of FundingK.M. Denton (APP1041844) was supported by a Principal Research Fellowship from the National Health and Medical Council of Australia.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors nor the American Heart Association.For Sources of Funding and Disclosures, see page 304.Correspondence to: Kate M Denton, 26 Innovation Walk, Clayton, Monash University, VIC Australia 3800. Email kate.[email protected]eduReferences1. Garovic VD, Dechend R, Easterling T, Karumanchi SA, McMurtry Baird S, Magee LA, Rana S, Vermunt JV, August P. Hypertension in pregnancy: diagnosis, blood pressure goals, and pharmacotherapy: a scientific statement from the American Heart Association.Hypertension. 2022; 79:e21–e41. doi: 10.1161/HYP.0000000000000208LinkGoogle Scholar2. Reyes LM, Usselman CW, Davenport MH, Steinback CD. Sympathetic nervous system regulation in human normotensive and hypertensive pregnancies.Hypertension. 2018; 71:793–803. doi: 10.1161/HYPERTENSIONAHA.117.10766LinkGoogle Scholar3. Badrov MB, Yoo JK, Hissen SL, Nelson DB, Shoemaker JK, Fu Q. Sympathetic action potential firing and recruitment patterns are abnormal in gestational hypertension.Hypertension. 2023; 80:291–301.doi: 10.1161/HYPERTENSIONAHA.122.19754LinkGoogle Scholar4. Salmanpour A, Brown LJ, Shoemaker JK. Spike detection in human muscle sympathetic nerve activity using a matched wavelet approach.J Neurosci Methods. 2010; 193:343–355. doi: 10.1016/j.jneumeth.2010.08.035CrossrefMedlineGoogle Scholar5. Greenwood JP, Scott EM, Walker JJ, Stoker JB, Mary DA. The magnitude of sympathetic hyperactivity in pregnancy-induced hypertension and preeclampsia.Am J Hypertens. 2003; 16:194–199. doi: 10.1016/s0895-7061(02)03256-9CrossrefMedlineGoogle Scholar6. Greenwood JP, Stoker JB, Walker JJ, Mary DA. Sympathetic nerve discharge in normal pregnancy and pregnancy-induced hypertension.J Hypertens. 1998; 16:617–624. doi: 10.1097/00004872-199816050-00009CrossrefMedlineGoogle Scholar7. Badrov MB, Park SY, Yoo JK, Hieda M, Okada Y, Jarvis SS, Stickford AS, Best SA, Nelson DB, Fu Q. Role of corin in blood pressure regulation in normotensive and hypertensive pregnancy.Hypertension. 2019; 73:432–439. doi: 10.1161/HYPERTENSIONAHA.118.12137LinkGoogle Scholar8. Reyes LM, Usselman CW, Khurana R, Chari RS, Stickland MK, Davidge ST, Julian CG, Steinback CD, Davenport MH. Preeclampsia is not associated with elevated muscle sympathetic reactivity.J Appl Physiol. 2021; 130:139–148. doi: 10.1152/japplphysiol.00646.2020CrossrefMedlineGoogle Scholar9. Geelhoed JJM, Fraser A, Tilling K, Benfield L, Davey Smith G, Sattar N, Nelson SM, Lawlor DA. Preeclampsia and gestational hypertension are associated with childhood blood pressure independently of family adiposity measures.Circulation. 2010; 122:1192–1199. doi: 10.1161/CIRCULATIONAHA.110.936674LinkGoogle Scholar10. Li J, LaMarca B, Reckelhoff JF. A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model.Am J Phys Heart Circ Phys. 2012; 303:H1–H8.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesSympathetic Action Potential Firing and Recruitment Patterns Are Abnormal in Gestational HypertensionMark B. Badrov, et al. Hypertension. 2023;80:291-301 February 2023Vol 80, Issue 2 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.122.20181PMID: 36652532 Originally publishedJanuary 18, 2023 KeywordshypertensionmorbiditypregnancymortalityEditorialsPDF download Advertisement SubjectsBlood PressureCerebrovascular Disease/StrokeHigh Blood Pressure