Temporal Patterns in Sheep Fetal Heart Rate Variability Correlate to Systemic Cytokine Inflammatory Response: A Methodological Exploration of Monitoring Potential Using Complex Signals Bioinformatics

Abstract

Fetal inflammation is associated with increased risk for postnatal organ injuries. No means of early detection exist. We hypothesized that systemic fetal inflammation leads to distinct alterations of fetal heart rate variability (fHRV). We tested this hypothesis deploying a novel series of approaches from complex signals bioinformatics. In chronically instrumented near-term fetal sheep, we induced an inflammatory response with lipopolysaccharide (LPS) injected intravenously (n = 10) observing it over 54 hours; seven additional fetuses served as controls. Fifty-one fHRV measures were determined continuously every 5 minutes using Continuous Individualized Multi-organ Variability Analysis (CIMVA). CIMVA creates an fHRV measures matrix across five signal-analytical domains, thus describing complementary properties of fHRV. We implemented, validated and tested methodology to obtain a subset of CIMVA fHRV measures that matched best the temporal profile of the inflammatory cytokine IL-6. In the LPS group, IL-6 peaked at 3 hours. For the LPS, but not control group, a sharp increase in standardized difference in variability with respect to baseline levels was observed between 3 h and 6 h abating to baseline levels, thus tracking closely the IL-6 inflammatory profile. We derived fHRV inflammatory index (FII) consisting of 15 fHRV measures reflecting the fetal inflammatory response with prediction accuracy of 90%. Hierarchical clustering validated the selection of 14 out of 15 fHRV measures comprising FII. We developed methodology to identify a distinctive subset of fHRV measures that tracks inflammation over time. The broader potential of this bioinformatics approach is discussed to detect physiological responses encoded in HRV measures.

Cardiorespiratory Alterations in a Newborn Ovine Model of Systemic Inflammation Induced by Lipopolysaccharide Injection

“…Although several explanations might account for the fact that an increase in IL-8 and TNF-α mRNA was not detected in all lambs 6 h after LPS injection, the interindividual variability of the time lag between LPS injection and the inflammatory response is the most likely. Past studies in fetal lambs reported that the highest serum level of IL-6 and TNF-α was measured between 3 and 6 h after systemic injection of LPS in fetal lambs (Durosier et al, 2015;Herry et al, 2016). Given the expectation that cytokine production and release by the nervous system will peak later on, our 6-h timepoint might be too early to observe a consistent increase in cytokine mRNA expression in the lambs' brainstem.…”

Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?

“…It is also of interest that given the existence of data demonstrating that the extent of HRV suppression correlates with the levels of systemic inflammation (Durosier et al 2015; Herry et al 2016) (review (Cooper et al 2015)), that HRV parameters could act as surrogate markers of systemic inflammation, which could potentially prove to be objective biomarkers for CFS patients in the early stages of their illness (Durosier et al 2015). However, low HRV values are also seen in patients suffering from major depressive disorder (Brunoni et al 2013), possibly as a result of associated high levels of peripheral PICs (reviewed (Berk et al 2013)) and hence HRV values are unlikely to be able to differentiate patients with CFS from those with a similar symptom presentation as a result of major depressive disorder.…”

Saving the brain one heartbeat at a time

“…; Herry et al . ). The study by Yamaguchi et al ., underscored in their discussion of HRV skewness findings, highlights the need for novel HRV approaches capturing the complex HRV response to HI injury or other insults resulting in perinatal brain injury that can benefit from early therapeutic intervention.…”