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In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension

Clinical trials evaluating the efficacy of chronic electrical stimulation of the carotid baroreflex for the treatment of hypertension (HTN) are ongoing. However, the mechanisms by which this device lowers blood pressure (BP) are unclear, and it is uncertain which patients are most likely to receive...

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Autores principales: Clemmer, John S., Pruett, W. Andrew, Hester, Robert L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601446/
https://www.ncbi.nlm.nih.gov/pubmed/34793497
http://dx.doi.org/10.1371/journal.pone.0259917
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author Clemmer, John S.
Pruett, W. Andrew
Hester, Robert L.
author_facet Clemmer, John S.
Pruett, W. Andrew
Hester, Robert L.
author_sort Clemmer, John S.
collection PubMed
description Clinical trials evaluating the efficacy of chronic electrical stimulation of the carotid baroreflex for the treatment of hypertension (HTN) are ongoing. However, the mechanisms by which this device lowers blood pressure (BP) are unclear, and it is uncertain which patients are most likely to receive clinical benefit. Mathematical modeling provides the ability to analyze complicated interrelated effects across multiple physiological systems. Our current model HumMod is a large physiological simulator that has been used previously to investigate mechanisms responsible for BP lowering during baroreflex activation therapy (BAT). First, we used HumMod to create a virtual population in which model parameters (n = 335) were randomly varied, resulting in unique models (n = 6092) that we define as a virtual population. This population was calibrated using data from hypertensive obese dogs (n = 6) subjected to BAT. The resultant calibrated virtual population (n = 60) was based on tuning model parameters to match the experimental population in 3 key variables: BP, glomerular filtration rate, and plasma renin activity, both before and after BAT. In the calibrated population, responses of these 3 key variables to chronic BAT were statistically similar to experimental findings. Moreover, blocking suppression of renal sympathetic nerve activity (RSNA) and/or increased secretion of atrial natriuretic peptide (ANP) during BAT markedly blunted the antihypertensive response in the virtual population. These data suggest that in obesity-mediated HTN, RSNA and ANP responses are key factors that contribute to BP lowering during BAT. This modeling approach may be of value in predicting BAT responses in future clinical studies.
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spelling pubmed-86014462021-11-19 In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension Clemmer, John S. Pruett, W. Andrew Hester, Robert L. PLoS One Research Article Clinical trials evaluating the efficacy of chronic electrical stimulation of the carotid baroreflex for the treatment of hypertension (HTN) are ongoing. However, the mechanisms by which this device lowers blood pressure (BP) are unclear, and it is uncertain which patients are most likely to receive clinical benefit. Mathematical modeling provides the ability to analyze complicated interrelated effects across multiple physiological systems. Our current model HumMod is a large physiological simulator that has been used previously to investigate mechanisms responsible for BP lowering during baroreflex activation therapy (BAT). First, we used HumMod to create a virtual population in which model parameters (n = 335) were randomly varied, resulting in unique models (n = 6092) that we define as a virtual population. This population was calibrated using data from hypertensive obese dogs (n = 6) subjected to BAT. The resultant calibrated virtual population (n = 60) was based on tuning model parameters to match the experimental population in 3 key variables: BP, glomerular filtration rate, and plasma renin activity, both before and after BAT. In the calibrated population, responses of these 3 key variables to chronic BAT were statistically similar to experimental findings. Moreover, blocking suppression of renal sympathetic nerve activity (RSNA) and/or increased secretion of atrial natriuretic peptide (ANP) during BAT markedly blunted the antihypertensive response in the virtual population. These data suggest that in obesity-mediated HTN, RSNA and ANP responses are key factors that contribute to BP lowering during BAT. This modeling approach may be of value in predicting BAT responses in future clinical studies. Public Library of Science 2021-11-18 /pmc/articles/PMC8601446/ /pubmed/34793497 http://dx.doi.org/10.1371/journal.pone.0259917 Text en © 2021 Clemmer et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Clemmer, John S.
Pruett, W. Andrew
Hester, Robert L.
In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension
title In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension
title_full In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension
title_fullStr In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension
title_full_unstemmed In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension
title_short In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension
title_sort in silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601446/
https://www.ncbi.nlm.nih.gov/pubmed/34793497
http://dx.doi.org/10.1371/journal.pone.0259917
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