Nonlinear analysis of heart rhythm in preeclampsia: a route for translational clinical applications in neuroinflammation

Abstract

Preeclampsia is a pregnancy-specific condition which gets detected through hypertension and excessive protein excretion in urine. While preeclampsia used to be regarded as a self-limiting maternal condition which resolved with the delivery of the placenta, it is nowadays considered a complex and multifactorial disease that affects the offspring. Unfortunately, the etiology and pathophysiology of this multifaceted disorder remain elusive. Recent findings have confirmed that an altered maternal autonomic function may play a vital role in developing preeclampsia in conjunction with an imbalanced maternal immune system. Additionally, further evidence supports the crucial role of an exacerbated immune response driven by a non-infectious trigger during preeclampsia. Therefore, as a sterile inflammation, the elucidation of the neuroinflammatory mechanisms of preeclampsia warrants obtaining relevant knowledge suitable for translational clinical applications.Heart rate variability (HRV) is an affordable and non-invasive method for indirectly assessing the autonomic nervous system and the cholinergic anti-inflammatory pathway (CAP). Notably, the nonlinear analysis of HRV offers novel indexes to explore the neuroimmune interactions in diverse preclinical and clinical settings of inflammation. Given that the dynamics of HRV is nonlinear in health, we hypothesized that a neuroinflammatory condition in preeclampsia might be associated with changes in nonlinear features of maternal and fetal HRV. Thus, the present review aims to present evidence of the potential changes in maternal-fetal HRV associated with neuroinflammatory modifications in preeclamptic women. We considered that there is still a need for assessing the nonlinear features of maternal and fetal HRV as complementary biomarkers of inflammation in this population in future studies, being a potential route for translational clinical applications.

Keywords: Autonomic nervous system; Neuroimmunomodulation; Pre-eclampsia; Pregnancy, heart rate.

Fig. 1

Preeclampsia etiology or exacerbation may be mediated by an upregulated sterile inflammation, it may be initiated by molecules in the host organism known as damage associated molecular patterns (DAMPs). In addition to DAMPs, the upregulation of this sterile inflammation is produced by an altered immune response in conjunction with autonomic dysfunctions. Particularly, immune alterations are characterized by the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) and decrease of anti-inflammatory cytokines such as interleukin-4 (IL-4) and interleukin-10 (IL-10). Finally, autonomic dysfunctions may involve diminished acetylcholine (ACh) synthesis, lower vagal tone, downregulation of both alpha 7 nicotinic acetylcholine receptor (α7nAChR) and cholinergic anti-inflammatory pathway (CAP)

Fig. 2

Alterations in preeclampsia may involve increased cardiac sympathetic activity, decreased cardiac parasympathetic activity, and reduced complexity of heart rate fluctuations. These alterations may produce changes in nonlinear features of the maternal or fetal heart rate variability (mHRV and fHRV, respectively). A downregulated maternal cholinergic anti-inflammatory pathway (CAP) may result in a high pro-inflammatory state in the mother and fetus (increased levels of tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], and other pro-inflammatory cytokines). The assessment of nonlinear features of heart rate variability (HRV) is a potential tool for exploring the neuroinflammatory interactions in the maternal-fetal dyad