Vagus Nerve Stimulation for Treatment of Inflammation: Systematic Review of Animal Models and Clinical Studies

Key points We introduce a technique to test whether intrinsic fetal heart rate variability (iFHRV) exists and we show the utility of the technique by testing the hypothesis that iFHRV is affected by chronic fetal hypoxia, one of the most common adverse outcomes of human pregnancy complicated by fetal growth restriction. Using an established late gestation ovine model of fetal development under chronic hypoxic conditions, we identify iFHRV in isolated fetal hearts and show that it is markedly affected by hypoxic pregnancy. Therefore, the isolated fetal heart has intrinsic variability and carries a memory of adverse intrauterine conditions experienced during the last third of pregnancy. Abstract Fetal heart rate variability (FHRV) emerges from influences of the autonomic nervous system, fetal body and breathing movements, and from baroreflex and circadian processes. We tested whether intrinsic heart rate variability (iHRV), devoid of any external influences, exists in the fetal period and whether it is affected by chronic fetal hypoxia. Chronically catheterized ewes carrying male singleton fetuses were exposed to normoxia (n = 6) or hypoxia (10% inspired O2, n = 9) for the last third of gestation (105–138 days of gestation (dG); term ∼145 dG) in isobaric chambers. At 138 dG, isolated hearts were studied using a Langendorff preparation. We calculated basal intrinsic FHRV (iFHRV) indices reflecting iFHRV's variability, predictability, temporal symmetry, fractality and chaotic behaviour, from the systolic peaks within 15 min segments in each heart. Significance was assumed at P < 0.05. Hearts of fetuses isolated from hypoxic pregnancy showed approximately 4‐fold increases in the Grid transformation as well as the AND similarity index (sgridAND) and a 4‐fold reduction in the scale‐dependent Lyapunov exponent slope. We also detected a 2‐fold reduction in the Recurrence quantification analysis, percentage of laminarity (pL) and recurrences, maximum and average diagonal line (dlmax, dlmean) and the Multiscale time irreversibility asymmetry index. The iHRV measures dlmax, dlmean, pL and sgridAND correlated with left ventricular end‐diastolic pressure across both groups (average R2 = 0.38 ± 0.03). This is the first evidence that iHRV originates in fetal life and that chronic fetal hypoxia significantly alters it. Isolated fetal hearts from hypoxic pregnancy exhibit a time scale‐dependent higher complexity in iFHRV.

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“…We refer to Kwan et al . () and Herry et al . () where we introduce the notion of vagus code in vagus electroneurogram (i.e.…”

Section: Discussionmentioning

confidence: 86%

First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy

Frasch

Herry

Niu

et al. 2020

The Journal of Physiology

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“…The latter could be single and ensemble recordings of the electrical pacemaker cells, followed by their analysis and comparison to the indirect observations derived from HRV. We refer to Kwan et al (2016) and Herry et al (2019) where we introduce the notion of vagus code in vagus electroneurogram (i.e. the direct observation) and attempt a more detailed discussion of the indirect observations.…”

Section: Discussionmentioning

confidence: 99%

First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy

Frasch

Herry

Niu

et al. 2018

Preprint

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Heart rate variability (HRV) is an important indicator of health and disease, yet its physiological origins are poorly understood. The contribution of intrinsic and extrinsic sources to HRV is not known. In a near-term fetal sheep model, we aimed to identify fetal HRV measures reflecting intrinsic contributions to HRV. Ex vivo Langendorff preparation was used to record intrinsic HRV in animals who were normoxic or hypoxic in vivo. We identify the intrinsic HRV in isolated hearts from fetal sheep in late gestation and how it is affected by chronic fetal hypoxia. Significance StatementHeart rate variability (HRV) is an important indicator of health and disease, yet its physiological origins are poorly understood. Both, the heart, intrinsically, and extrinsic systems, such as the brain, are hypothesized to contribute to HRV. In a near-term fetal sheep model of human development, we identified fetal HRV components reflecting intrinsic contributions to HRV. In addition, we show that these intrinsic HRV components carry memory of chronic oxygen deprivation the fetus experienced during the last third of gestation.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/242107 doi: bioRxiv preprint first posted online Jan. 22, 2018; 3 IntroductionFetal heart rate (FHR) monitoring is widely used clinically during labour, although its ability to identify fetuses at risk of severe metabolic acidosis is poor.(1) It is established that normal FHR variability (fHRV) represents a complex, nonlinear integration of the sympathetic and parasympathetic nervous system activities. Fetal body and breathing movements, baroreflex and circadian processes also influence HRV.(2,3,4-6) There is also some evidence that intrinsic pacemaker rhythms of the sino-atrial node affect HRV in critically ill adults. (7) However, whether intrinsic HRV (iHRV) exists in the fetal period and whether this is affected by chronic fetal hypoxia has never been tested. Here, we show iHRV in isolated hearts from fetal sheep in late gestation. We also show that chronic fetal hypoxia has significant effects on iHRV.

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“…In other words, vagotomy perturbs such spontaneous activity further reflecting underlying HRV fluctuations which represent a proxy to the vagus code embedded in fHRV. (Kwan et al , 2016) In sham animals, most fHRV measures recovered with complexity and variability increasing at 72h when compared to pre or post-surgery time points. However, 30-35% of fHRV measures showed a loss of complexity.…”

Section: Discussionmentioning

confidence: 90%

“…(Iberall & McCulloch, 1968;Thayer & Sternberg, 2006;Macklem & Seely, 2010) We use this experimental approach to identify a subset of fHRV measures that characterise vagal contributions, the vagus code. (Kwan et al , 2016) We present a methodological tool box to do that borrowing from methodologies used in genomics.…”

Section: Introductionmentioning

confidence: 99%

Vagal contributions to fetal heart rate variability: an omics approach

et al. 2019

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Fetal heart rate variability (fHRV) is an important indicator of health and disease, yet its physiological origins, neural contributions in particular, are not well understood. We aimed to develop novel experimental and data analytical approaches to identify fHRV measures reflecting the vagus nerve contributions to fHRV. In near-term ovine fetuses, a comprehensive set of 46 fHRV measures was computed from fetal pre-cordial electrocardiogram recorded during surgery and 72 hours later without (n=24) and with intra-surgical bilateral cervical vagotomy (n=15). The fetal heart rate did not change due to vagotomy. We identify fHRV measures specific to the vagal modulation of fHRV: Multiscale time irreversibility asymmetry index (AsymI), Detrended fluctuation analysis (DFA) α 1 , Kullback-Leibler permutation entropy (KLPE) and Scale dependent Lyapunov exponent slope (SDLE α). We provide a systematic delineation of vagal contributions to fHRV across signal-analytical domains which should be relevant for the emerging field of bioelectronic medicine and the deciphering of the "vagus code". Our findings also have clinical significance for in utero monitoring of fetal health during surgery. Key points• Fetal surgery causes a complex pattern of changes in heart rate variability measures with overall reduction of complexity or variability • At 72 hours after surgery, many of the HRV measures recover and this recovery is delayed by an intrasurgical cervical bilateral vagotomy • We identify HRV pattern representing complete vagal withdrawal that can be understood as part of "HRV code", rather than any single HRV measure • We identify HRV biomarkers of recovery from fetal surgery and discuss the effect of anticholinergic medication on this recovery al. , 2011;Sassi et al. , 2015) While some of these techniques capture properties of time series' variability that are correlated, most offer a unique aspect of variability by characterizing different mathematical properties of the signals. They include measures characterizing the statistical properties (e.g., standard deviation, root mean square of successive differences of R-R intervals of electrocardiogram (ECG), RMSSD), the informational complexity (e.g., entropy measures), the pattern of variations across time scales (i.e., time-invariant features such as fractal measures, power law exponents) or the energy contained in the signal (e.g., spectral measures). Researchers generally agree that a plurality of techniques offers the most complete evaluation. (Goldberger, 1996;Goldberger et al. , 2002) An important underlying assumption about studying biological variability is that it has predictive properties about physiological systems from which it emerges. Hence, variability properties are a form of biological code, taking place on different scales in space and time. While the time component can be taken literally, the space component can represent different organs and regions of the body contributing to the properties of a variability pattern in question. The space component can also...

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Vagus Nerve Stimulation for Treatment of Inflammation: Systematic Review of Animal Models and Clinical Studies

Abstract: Cite this article as: Kwan H, et al. (2016) Vagus nerve stimulation for treatment of inflammation: Systematic review of animal models and clinical studies. Bioelectron. Med.

Cited by 56 publications

References 58 publications

First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy

First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy

First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy

Vagal contributions to fetal heart rate variability: an omics approach

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