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• W4205422790 abstract "Letter to the EditorReply to Fadel et al.Massimo Nardone, Lauro C. Vianna, and Philip J. MillarMassimo NardoneDepartment of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada, Lauro C. ViannaNeuroVASQ-Integrative Physiology Laboratory, Faculty of Physical Education, University of Brasilia, Brasilia, Brazil, and Philip J. MillarDepartment of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, CanadaToronto General Research Institute, Toronto General Hospital, Toronto, Ontario, CanadaPublished Online:19 Jan 2022https://doi.org/10.1152/ajpregu.00265.2021MoreSectionsPDF (486 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations reply: We thank Dr. Fadel and colleagues (1) for their interest and commentary on our study of the relationships between measures of signal-averaged sympathetic transduction of blood pressure (BP) and resting muscle sympathetic nerve activity (MSNA) in healthy young adults and the development of a method for normalizing differences in MSNA burst frequency between individuals for sympathetic transduction analyses (2). We will address several important points raised in their Letter to the Editor and incorporate the results of our recent analysis showing the influence of BP oscillations on sympathetic transduction of BP (3).First, we want to clarify that we do not believe that resting MSNA is the primary determinant of signal-averaged sympathetic transduction of BP. As noted, considerable variability in sympathetic transduction of BP responses exists between individuals with a resting MSNA burst frequency below ∼30–35 bursts/min, and we concur that this likely reflects interindividual differences in physiological parameters, such as adrenergic sensitivity or norepinephrine and coneurotransmitter release. Instead, our contention is that results of the regression analyses, revealing that resting MSNA burst frequency can explain ∼18%–44% of the variability in sympathetic transduction of BP (depending on the measure used), represent a nontrivial factor that could confound interpretation of the results, depending on the characteristics of the populations studied. This is particularly relevant when comparing healthy controls with diseased populations with large differences in resting MSNA (4).Second, we acknowledge that our study did not determine whether the negative relationship between sympathetic transduction of BP and resting MSNA represents a physiological compensatory adaptation, methodological limitation of the signal-averaging technique, or some combination of both. Thus, the context for needing to apply a normalization of MSNA may not be readily apparent, which is why we suggested both absolute and normalized values be reported in parallel to offer greater insight as new studies come forward addressing this critical question. Stimulated by reviewer feedback of our paper, we completed more in-depth analyses and reported recently how the timing of each burst relative to oscillations in BP can influence the signal-averaged sympathetic transduction of BP (3). We found that when an MSNA burst occurs at a higher BP level the resultant signal-averaged sympathetic transduction of BP can appear to cause a decrease in BP, which would be discordant to the normal physiological response to vasoconstriction. Individuals with more bursts occurring at higher BP levels (a consequence of a higher resting MSNA burst frequency) thus average more “negative” or small transduction responses leading to smaller overall transduction values and the negative correlation with resting MSNA. Only when examining the difference (Δ) in BP responses between cardiac cycles with and without an MSNA burst does a physiological “rise” in BP become apparent when an MSNA burst fires at higher BP levels (3). In our view, these results demonstrate an important confounding factor of the signal-averaging technique, which can require normalization [resting MSNA burst frequency represents a proxy of the proportion of bursts occurring at higher BP levels (3)] or the incorporation of the BP responses to nonburst cardiac cycles to enable accurate physiological interpretations between individuals with differing MSNA. Reanalysis of our data (2) shows that the difference in BP responses between cardiac cycles with and without an MSNA burst (as a measure of sympathetic transduction) is unrelated to resting MSNA burst frequency (r2 = 0.01, P = 0.22).Third, we believe the critique that “normalization to resting MSNA does not change that an individual with low sympathetic transduction still has low transduction” is valid only if the method captures the “true” physiological response and is not influenced by measurement error. To conceptualize the challenge of comparing sympathetic transduction of BP between individuals with different resting MSNA, we selected two participants from our prior work (2) who had similar measures of sympathetic transduction of BP but differences in resting MSNA burst frequency normally encountered in most laboratories (Fig. 1). We performed signal-averaged sympathetic transduction of BP analyses across separate tertiles of diastolic BP that, when considering the BP responses to nonburst cardiac cycles, reveals the participant with higher resting MSNA displays larger sympathetic transduction of BP. However, since the individual with a higher resting MSNA has a larger proportion of bursts firing in the highest tertile of diastolic BP (which have negative transduction or drops in BP), the absolute sympathetic transduction of BP response was similar between individuals. This is not a unique example but the norm for comparisons in our data. Fadel et al. (1) raise concerns that normalizing sympathetic transduction of BP could remove physiological information pertaining to the influence of resting MSNA on adrenergic sensitivity. We cannot exclude this possibility but highlight, in the aforementioned study, that after a 3-μg (100 mL)−1·min−1 dose of intra-arterial tyramine in participants with arteriovenous measures of norepinephrine (to confirm efficacy of the sympathomimetic), forearm blood flow was reduced similarly by ∼25%–30% in participants with low and high resting MSNA burst frequency (see Fig. 4 in Ref. 5). This level may be more physiologically relevant for translation to resting signal-averaging techniques versus the higher doses, which represent responses to more intense sympathetic stress. Overall, we agree that more work needs to be done to better understand the factors contributing to inter-individual differences in sympathetic transduction of BP, including the role of differences in the proportion of MSNA bursts at higher BP levels (3) as a methodological confounder for accurate physiological interpretation.Figure 1.A: data from Nardone et al. (2) displaying the relationship between resting muscle sympathetic nerve activity (MSNA) burst frequency and sympathetic transduction of diastolic blood pressure (BP) in 107 healthy participants. Blue and red dots highlight two participants with identical sympathetic transduction but different resting MSNA. B: sympathetic transduction across tertiles of diastolic BP. From left to right: 1) Sympathetic transduction in the first participant (blue). 2) Sympathetic transduction in the second participant (red). Colored lines represent Δ diastolic BP response to MSNA bursts, gray lines represent Δ diastolic BP response to nonburst cardiac cycles, and gray shaded areas represent the difference between both responses. 3) Mean sympathetic transduction of BP responses for both participants. 4) Proportion of MSNA bursts firing at each operating pressure level. C: summary data of participants resting MSNA burst frequency and conventional and normalized sympathetic transduction.Download figureDownload PowerPointFinally, we agree with Fadel and colleagues (6) that the signal-averaged sympathetic transduction technique represents a valuable tool to understand neurocardiovascular regulation both within and across different cohorts, to which they have made seminal contributions. Our recent work (2, 3) has sought to better understand the limitations of the technique to aid in the physiological interpretation of data. Our analysis of normalizing for resting MSNA was also done to highlight the nonlinear nature of the relationship between sympathetic transduction of BP across a large range of resting MSNA levels. We note that not all studies may be affected by methodological effects, depending on the underlying participant characteristics, and recommended that each study test and report the relationship between resting MSNA and sympathetic transduction of BP to determine whether normalization is warranted (2). Incorporating our recent findings (3), the need for normalization may be unnecessary if analyses account for the proportions of MSNA bursts occurring at different BP levels or examine the differences in BP responses between cardiac cycles with and without MSNA bursts. We look forward to future studies that help to answer some of the key methodological and physiological questions regarding the assessment of sympathetic transduction of BP (and vascular conductance) in humans.GRANTSP.J.M. is supported by a Natural Science and Engineering Research Council of Canada (NSERC) Discovery Grant, the Canada Foundation for Innovation, the Ontario Ministry of Research, Innovation and Science, an Early Researcher Award by the Ontario Ministry of Economic Development, Job Creation and Trade, and the American Physiological Society Arthur C. Guyton Award for Excellence in Integrative Physiology. L.C.V. is supported by the National Council for Scientific and Technological Development (CNPq; Grants: 307293/2019-0 and 431740/2018-6) and American Physiological Society Arthur C. Guyton Award for Excellence in Integrative Physiology. M.N. was supported by the Canadian Institute of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarship.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSM.N., L.C.V., and P.J.M. drafted manuscript; M.N., L.C.V., and P.J.M. edited and revised manuscripts; M.N., L.C.V., and P.J.M. approved final version of manuscript. REFERENCES1. Fadel PJ, Young BE, Keller DM. Sympathetic transduction: let’s not forget about the physiology. Am J Physiol Regul Integr Comp Physiol 321: R634–R635, 2021. doi:10.1152/ajpregu.00212.2021.Link | ISI | Google Scholar2. Nardone M, Incognito AV, Kathia MM, Omazic LJ, Lee JB, Teixeira AL, Xie S, Vianna LC, Millar PJ. Signal-averaged resting sympathetic transduction of blood pressure: is it time to account for prevailing muscle sympathetic burst frequency? Am J Physiol Regul Integr Comp Physiol 321: R484–R494, 2021. doi:10.1152/ajpregu.00131.2021.Link | ISI | Google Scholar3. Nardone M, Katerberg C, Incognito AV, Teixeira AL, Vianna LC, Millar PJ. Blood pressure oscillations impact signal-averaged sympathetic transduction of blood pressure: implications for the association with resting sympathetic outflow. Am J Physiol Heart Circ Physiol 321: H798–H806, 2021. doi:10.1152/ajpheart.00422.2021.Link | ISI | Google Scholar4. Kobetic MD, Burchell AE, Ratcliffe LEK, Neumann S, Adams ZH, Nolan R, Nightingale AK, Paton JFR, Hart EC. Sympathetic-transduction in untreated hypertension. J Hum Hypertens, 2021. doi:10.1038/s41371-021-00578-5.Crossref | PubMed | ISI | Google Scholar5. Charkoudian N, Joyner MJ, Sokolnicki LA, Johnson CP, Eisenach JH, Dietz NM, Curry TB, Wallin BG. Vascular adrenergic responsiveness is inversely related to tonic activity of sympathetic vasoconstrictor nerves in humans. J Physiol 572: 821–827, 2006. doi:10.1113/jphysiol.2005.104075.Crossref | PubMed | ISI | Google Scholar6. Young BE, Greaney JL, Keller DM, Fadel PJ. Sympathetic transduction in humans: recent advances and methodological considerations. Am J Physiol Heart Circ Physiol 320: H942–H953, 2021. doi:10.1152/ajpheart.00926.2020.Link | ISI | Google ScholarAUTHOR NOTESCorrespondence: P. J. Millar ([email protected]ca). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Related ArticlesSympathetic transduction: let’s not forget about the physiology 05 Oct 2021American Journal of Physiology-Regulatory, Integrative and Comparative PhysiologyCited ByAttenuated Sympathetic Blood Pressure Transduction in Patients With Treated Heart Failure With Reduced Ejection FractionHypertension, Vol. 79, No. 12Sympathetic transduction of blood pressure during graded lower body negative pressure in young healthy adultsMassimo Nardone, Carlin Katerberg, André L. Teixeira, Jordan B. Lee, Julian C. Bommarito, and Philip J. Millar25 May 2022 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 322, No. 6 More from this issue > Volume 322Issue 2February 2022Pages R123-R125 Crossmark Copyright & PermissionsCopyright © 2022 the American Physiological Society.https://doi.org/10.1152/ajpregu.00265.2021PubMed35043690History Received 21 October 2021 Accepted 1 November 2021 Published online 19 January 2022 Published in print 1 February 2022 Keywordsblood pressuresympathetic transduction Metrics" @default.
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