Temporal Patterns in Sheep Fetal Heart Rate Variability Correlate to Systemic Cytokine Inflammatory Response: A Methodological Exploration of Monitoring Potential Using Complex Signals Bioinformatics.
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.
Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, Canada.
Christophe L
CL
Herry
Centre de recherche en reproduction animale, l'Université de Montréal, St-Hyacinthe, QC, Canada.
Marina
http://orcid.org/0000-0002-4710-6334
M
Cortes
Department of Mathematics, University of Toronto, Toronto, ON, Canada.
Hau-Tieng
HT
Wu
Department of OBGYN and Department of Neurosciences, CHU Ste-Justine Research Centre, l'Université de Montréal, Montréal, QC, Canada.
Lucien D
LD
Durosier
Department of OBGYN and Department of Neurosciences, CHU Ste-Justine Research Centre, l'Université de Montréal, Montréal, QC, Canada.
Mingju
http://orcid.org/0000-0003-3380-7620
M
Cao
Clinical Sciences, CHUV, l'Université de Montréal, St-Hyacinthe, QC, Canada,4 Divisions of Thoracic Surgery and Critical Care Medicine, University of Ottawa, Ottawa, Canada.
Patrick
http://orcid.org/0000-0001-5229-3886
P
Burns
Clinical Sciences, CHUV, l'Université de Montréal, St-Hyacinthe, QC, Canada,4 Divisions of Thoracic Surgery and Critical Care Medicine, University of Ottawa, Ottawa, Canada.
André
A
Desrochers
Clinical Sciences, CHUV, l'Université de Montréal, St-Hyacinthe, QC, Canada,4 Divisions of Thoracic Surgery and Critical Care Medicine, University of Ottawa, Ottawa, Canada.
Gilles
G
Fecteau
Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, Canada.|Clinical Sciences, CHUV, l'Université de Montréal, St-Hyacinthe, QC, Canada,4 Divisions of Thoracic Surgery and Critical Care Medicine, University of Ottawa, Ottawa, Canada.
Andrew J E
AJ
Seely
Department of OBGYN and Department of Neurosciences, CHU Ste-Justine Research Centre, l'Université de Montréal, Montréal, QC, Canada.|Centre de recherche en reproduction animale, l'Université de Montréal, St-Hyacinthe, QC, Canada.
Martin G
MG
Frasch
D000818:Animals; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D005260:Female; D005323:Fetal Monitoring / Q000379:methods*; D006340:Heart Rate, Fetal / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D011247:Pregnancy; D025341:Principal Component Analysis; D015203:Reproducibility of Results; D034561:Sheep, Domestic
D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides