Muscle Sympathetic Action Potential Firing Patterns During Normotensive and Hypertensive Pregnancy: A Longitudinal Assessment

HomeCirculationVol. 147, No. 7Muscle Sympathetic Action Potential Firing Patterns During Normotensive and Hypertensive Pregnancy: A Longitudinal Assessment Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBMuscle Sympathetic Action Potential Firing Patterns During Normotensive and Hypertensive Pregnancy: A Longitudinal Assessment Mark B. Badrov, Jeung-Ki Yoo, Sarah L. Hissen, Andrew W. D’Souza, David B. Nelson, J. Kevin Shoemaker and Qi Fu Mark B. BadrovMark B. Badrov https://orcid.org/0000-0001-7809-0729 Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas (M.B.B., J.-K.Y., S.L.H., Q.F.). University of Texas Southwestern Medical Center, Dallas (M.B.B., J.-K.Y., S.L.H., D.B.N., Q.F.). Department of Medicine, Toronto General Health Research Institute, University Health Network, Canada (M.B.B.). Search for more papers by this author , Jeung-Ki YooJeung-Ki Yoo https://orcid.org/0000-0003-1350-2491 Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas (M.B.B., J.-K.Y., S.L.H., Q.F.). University of Texas Southwestern Medical Center, Dallas (M.B.B., J.-K.Y., S.L.H., D.B.N., Q.F.). Search for more papers by this author , Sarah L. HissenSarah L. Hissen https://orcid.org/0000-0003-3181-6961 Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas (M.B.B., J.-K.Y., S.L.H., Q.F.). University of Texas Southwestern Medical Center, Dallas (M.B.B., J.-K.Y., S.L.H., D.B.N., Q.F.). Search for more papers by this author , Andrew W. D’SouzaAndrew W. D’Souza https://orcid.org/0000-0001-7024-0446 School of Kinesiology (A.W.D., J.K.S.), University of Western Ontario, London, Canada. Search for more papers by this author , David B. NelsonDavid B. Nelson University of Texas Southwestern Medical Center, Dallas (M.B.B., J.-K.Y., S.L.H., D.B.N., Q.F.). Search for more papers by this author , J. Kevin ShoemakerJ. Kevin Shoemaker School of Kinesiology (A.W.D., J.K.S.), University of Western Ontario, London, Canada. Department of Physiology and Pharmacology (J.K.S.), University of Western Ontario, London, Canada. Search for more papers by this author and Qi FuQi Fu Correspondence to: Qi Fu, MD, PhD, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, 7232 Greenville Avenue, Dallas, TX 75231. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4218-9126 Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas (M.B.B., J.-K.Y., S.L.H., Q.F.). University of Texas Southwestern Medical Center, Dallas (M.B.B., J.-K.Y., S.L.H., D.B.N., Q.F.). Search for more papers by this author Originally published13 Feb 2023https://doi.org/10.1161/CIRCULATIONAHA.122.062192Circulation. 2023;147:611–613Gestational hypertension (GH) represents a leading cause of maternal–fetal morbidity and mortality worldwide. Its pathogenesis remains to be fully elucidated, but accumulating evidence suggests that sympathetic neural dysregulation may play an important role.1,2 In a cross-sectional design, we recently demonstrated that during late pregnancy, women who develop GH display a marked augmentation of sympathetic action potential (AP) firing per integrated burst, as well as total AP firing frequency, compared with women with normal pregnancies.3 It remains unknown whether aberrant AP discharge also is present during early pregnancy in women who subsequently develop GH, when increased muscle sympathetic nerve activity (MSNA) burst frequency is already manifest,1 and how such firing patterns influence resting blood pressure (BP) throughout gestation. Therefore, we investigated prospectively the patterning of resting multiunit muscle sympathetic AP discharge throughout both normotensive and hypertensive pregnancies.Twenty-four otherwise healthy nonsmokers who were planning to become pregnant or were within the first 8 weeks of pregnancy participated after providing informed consent. Women were tested longitudinally before pregnancy (midluteal phase; n=12), during early (4 to 8 weeks of gestation; n=24) and late pregnancy (32 to 36 weeks of gestation; n=24), and postpartum (6 to 10 weeks after delivery; n=22). After delivery, women were divided into 2 groups: those with healthy, normal pregnancies (NP; n=18; early pregnancy: 31±5 years, 70±12 kg; late pregnancy: 81±12 kg) and those who developed GH after their late pregnancy testing (n=6; early pregnancy: 30±4 years, 81±22 kg; late pregnancy: 93±19 kg), diagnosed clinically, as detailed previously.1,3 None developed preeclampsia. The study received institutional review board approval (STU-012011-198). Parts of these data have been reported to address separate, unique hypotheses.1,3Heart rate, BP (electrosphygmomanometry), and MSNA (microneurography) were collected for 6 minutes during supine rest. Resting MSNA was analyzed from the traditionally measured, integrated neurogram and from our novel approach to extract APs from the filtered raw MSNA signal, using wavelet-based methodology.3 Multiunit AP firing patterns were quantified as the mean AP content per integrated burst (spikes/burst) and AP frequency (spikes/min).Resting mean BP was unchanged throughout gestation in NP (all P>0.05); in GH, it increased from early to late pregnancy (P<0.05) and thus was greater than NP during late pregnancy and postpartum (both P<0.05; Figure, A). Resting heart rate increased during late pregnancy in NP and GH (both P<0.05 versus prepregnancy), but no differences existed between groups throughout gestation (all P>0.05; Figure, B). MSNA burst frequency increased during late pregnancy in NP and GH (both P<0.05 versus prepregnancy); as anticipated,1 throughout early and late pregnancy, and postpartum, it was greater in GH (all P<0.05; Figure, C). During prepregnancy, the mean AP content per burst was similar between groups (P>0.05); it increased during late pregnancy in NP (P<0.05 versus prepregnancy), but in GH, it increased during both early and late pregnancy (both P<0.05 versus prepregnancy), before returning to prepregnancy levels in both groups postpartum (both P>0.05). Therefore, throughout early and late pregnancy, the mean AP content per burst was greater in GH (both P<0.05; Figure, D). Furthermore, AP frequency increased during late pregnancy in NP (both P<0.05 versus prepregnancy), whereas in GH, it increased during both early and late pregnancy (all P<0.05 versus prepregnancy), before returning to prepregnancy levels in both groups postpartum (both P>0.05). Therefore, throughout early and late pregnancy, AP frequency was greater in GH (all P<0.05; Figure, E). The change in AP frequency from early to late pregnancy was related directly to resting BP in late pregnancy (R2=0.32; P<0.01; Figure, F).Download figureDownload PowerPointFigure. Hemodynamic and sympathetic indexes throughout pregnancy. A, Mean arterial blood pressure (BP), (B) heart rate, (C) muscle sympathetic nerve activity (MSNA) burst frequency, (D) multiunit action potentials (APs) per integrated burst, and (E) AP frequency at supine rest before pregnancy (NP, n=9; gestational hypertension [GH], n=3), in early pregnancy (NP, n=18; GH, n=6), in late pregnancy (NP, n=18; GH, n=6), and after delivery (NP, n=17; GH, n=5) in women with healthy, normal pregnancies (NP; n=18) and in women who developed GH (n=6). Data are presented as mean±SD. F, Relationship between the change in AP frequency from early to late pregnancy and resting mean arterial BP in late pregnancy in women with NP (n=17) and in women who developed GH (n=5). *Significantly different from prepregnancy; P<0.05. †Significantly different from early pregnancy; P<0.05. αSignificantly different from NP; P<0.05. The effects of group and time were assessed with a repeated measures analysis using a mixed model design with Bonferroni-corrected post hoc procedures. In addition to the overall average effect, the slope and intercept were allowed to vary from participant to participant (random effect), thus providing a more robust analysis of longitudinal data sets through the ability to accommodate missing data points and model nonlinear, individual characteristics. Linear regression analyses were used to determine specific relationships between variables of interest. Statistical significance was set at P<0.05. All supporting data are available within the article.We demonstrate for the first time in a longitudinal manner the presence of aberrant multiunit sympathetic AP discharge patterns during early and late pregnancy in women who subsequently develop GH. Women with hypertensive pregnancies display a marked augmentation of within-burst AP firing and total AP firing frequency during early pregnancy (ie, within 8 weeks of gestation), both of which remain exaggerated throughout gestation. Conversely, such indexes are not elevated during early pregnancy in women who remain normotensive. Thus, the overall sympathetic burden in GH is dramatically larger when considering AP discharge behavior. During early pregnancy, the traditional metric of MSNA burst frequency was ~66% higher in GH than NP, whereas total AP firing frequency (the product of burst frequency and the number of APs firing per burst) was ~240% higher. This level of excess in GH persisted (and even increased) at late pregnancy and suggests that AP firing patterns represent a more sensitive measure to detect or predict pregnancy-related abnormalities.Furthermore, changes in total AP firing frequency from early to late pregnancy were related directly to resting BP in late pregnancy, providing evidence of a role for abnormal sympathetic AP patterning in the pathogenesis of GH. Notably, our findings suggest that the substrate for elevated BP—and a potential warning signal or biomarker for GH development—appears to be present as early as the first trimester. Considering the rise in global incidence,4 and the elevated and lasting morbidity associated with GH diagnosis,5 our results emphasize the importance of investigating potential sympathoinhibitory strategies aimed at reversing such disturbances early on during pregnancy in women at risk of GH.Article InformationAcknowledgmentsThe authors thank the volunteers for participation and Monique Roberts-Reeves and Rosemary Parker for laboratory assistance.Sources of FundingThis work was supported by the National Institutes of Health (grants R01HL142605 and R21HL088184), the American Heart Association Grant-In-Aid (13GRNT16990064), and Harry S. Moss Heart Trust Awards (2015-2020). Dr Badrov was supported by American Autonomic Society-Lundbeck and Canadian Institutes of Health Research Postdoctoral Fellowship Awards.Nonstandard Abbreviations and AcronymsAPaction potentialBPblood pressureGHgestational hypertensionMSNAmuscle sympathetic nerve activityNPnormal pregnancyDisclosures None.FootnotesThis manuscript was sent to Suzanne Oparil, MD, Guest Editor, for review by expert referees, editorial decision, and final disposition.For Sources of Funding and Disclosures, see page 613.Circulation is available at www.ahajournals.org/journal/circThis article is part of the Science Goes Red™ collection. Science Goes Red™ is an initiative of Go Red for Women®, the American Heart Association’s global movement to end heart disease and stroke in women.Correspondence to: Qi Fu, MD, PhD, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, 7232 Greenville Avenue, Dallas, TX 75231. Email qifu@texashealth.orgReferences1. 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: a prospective study.Hypertension. 2019; 73:432–439. doi: 10.1161/hypertensionaha.118.12137LinkGoogle Scholar2. Fu Q. Hemodynamic and electrocardiographic aspects of uncomplicated singleton pregnancy.Adv ExpMed Biol. 2018; 1065:413–431doi: 10.1007/978-3-319-77932-4_26CrossrefGoogle 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 [published online September 6, 2022].Hypertension.doi: 10.1161/HYPERTENSIONAHA.122.19754LinkGoogle Scholar4. Cameron NA, Everitt I, Seegmiller LE, Yee LM, Grobman WA, Khan SS. Trends in the incidence of new-onset hypertensive disorders of pregnancy among rural and urban areas in the United States, 2007 to 2019.J Am Heart Assoc. 2022; 11:23791. doi: 10.1161/JAHA.121.023791LinkGoogle Scholar5. Wen Lo CC, Lo ACQ, Leow SH, Fisher G, Corker B, Batho O, Morris B, Chowaniec M, Vladutiu CJ, Fraser A, et al. Future cardiovascular disease risk for women with gestational hypertension: a systematic review and meta-analysis.J Am Heart Assoc. 2020; 9:13991. doi: 10.1161/JAHA.119.013991LinkGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails February 14, 2023Vol 147, Issue 7 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.062192PMID: 36780388 Originally publishedFebruary 13, 2023 Keywordspregnancypregnancy-inducedhypertensionaction potentialsPDF download Advertisement SubjectsAutonomic Nervous SystemPregnancy