Impaired Vagal Activity in Long-COVID-19 Patients

Abstract

Long-COVID-19 refers to the signs and symptoms that continue or develop after the “acute COVID-19” phase. These patients have an increased risk of multiorgan dysfunction, readmission, and mortality. In Long-COVID-19 patients, it is possible to detect a persistent increase in D-Dimer, NT-ProBNP, and autonomic nervous system dysfunction. To verify the dysautonomia hypothesis in Long-COVID-19 patients, we studied heart rate variability using 12-lead 24-h ECG monitoring in 30 Long-COVID-19 patients and 20 No-COVID patients. Power spectral analysis of heart rate variability was lower in Long-COVID-19 patients both for total power (7.46 ± 0.5 vs. 8.08 ± 0.6; p < 0.0001; Cohens-d = 1.12) and for the VLF (6.84 ± 0.8 vs. 7.66 ± 0.6; p < 0.0001; Cohens-d = 1.16) and HF (4.65 ± 0.9 vs. 5.33 ± 0.9; p = 0.015; Cohens-d = 0.76) components. The LF/HF ratio was significantly higher in Long-COVID-19 patients (1.46 ± 0.27 vs. 1.23 ± 0.13; p = 0.001; Cohens-d = 1.09). On multivariable analysis, Long-COVID-19 is significantly correlated with D-dimer (standardized β-coefficient = 0.259), NT-ProBNP (standardized β-coefficient = 0.281), HF component of spectral analysis (standardized β-coefficient = 0.696), and LF/HF ratio (standardized β-coefficient = 0.820). Dysautonomia may explain the persistent symptoms in Long COVID-19 patients. The persistence of a procoagulative state and an elevated myocardial strain could explain vagal impairment in these patients. In Long-COVID-19 patients, impaired vagal activity, persistent increases of NT-ProBNP, and a prothrombotic state require careful monitoring and appropriate intervention.

Keywords: D-dimer; Long-COVID-19; NT-ProBNP; dysautonomia hypothesis; heart rate variability; procoagulative state.

Figure 1

Main relationship of HRV (SDNN, LF/HF ratio), D-Dimer, NT-ProBNP, and IL-6 in No-COVID-19 compared to Long-COVID-19 patients.

Figure 2

Routes of SARS-CoV-2 invasion. SARS-CoV-2 is mainly transmitted from one person to another by inhalation of droplets. SARS-CoV-2 enters the mucosal cells of the respiratory tract, conjunctiva, and gastrointestinal tract through ACE2 receptors. When the virus comes into contact with the ocular conjunctiva, it could reach the central nervous system via the trigeminal nerve. Although the hypothesis is still controversial, some authors believe that when SARS-CoV-2 comes into contact with the nasal mucosa, it reaches the brain through the olfactory nerve and that the vagus nerve, which innervates the respiratory system, the heart, the digestive system, the kidneys, bladder, uterus, and testicles, is a large route of transfer to the central nervous system. The virus enters the brain via neuronal retrograde transport up to the axonal terminal. SARS-CoV-2 also invades COVID-19 patients through the vasculature and lymphoid pathways. Once the virus has entered the circulation, it can invade the brain through blood-brain barrier breakdown. When the virus comes into contact with the host cell, the innate immune response activates the cytokine storm, particularly during ARDS hypoxia in patients with severe COVID-19. Cytokine storm leads to multi-organ failure (MOF) and damaged blood-brain barrier. With an intact blood-brain barrier, the passage of SARS-CoV-2 to the brain is unlikely [21,22]. This figure was created using the website https://app.biorender.com (accessed on 14 October 2021).

Figure 3

SARS-CoV-2 spreads by transsynaptic viral neuroinvasion from periphery to the brain. The retrograde transsynaptic viral spread occurs via a mechanism of endocytosis or exocytosis and the transport of vesicles occurs along the fast axonal microtubules. Axonal damage is expressed by the increased concentration of NfL in COVID-19 patients. The neuroinvasion of SARS-CoV-2 induces an excess of glutamate at the synaptic level. Moreover, high levels of inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin (IL)-1β released by activated inflammatory cells, including microglia, astroglia, and macrophages, lead to increases in synaptic glutamate concentrations. SARS-CoV-2 damages macrophages, microglia, and astrocytes. In fact, in COVID-19 patients even with moderate disease, it is possible to find increased glial fibrillary acid protein (GFAp) as a marker of astrocytic activation/injury. Effects of inflammatory molecules on astrocytic cell morphology leads to decreased ability to sequester and contain glutamate within the synapse, resulting in a spill-over of the glutamate into the extrasynaptic space. Increases in synaptic glutamate resulting from early inflammatory changes induced by SARS-CoV-2 invasion have been shown to induce overactivation of intrasynaptic ionotropic receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate receptors (NMDA), potentially contributing to excitotoxicity [28]. This figure was created using the website https://app.biorender.com (accessed on 14 October 2021).