Vagotomy accelerates the onset of symptoms during early disease progression and worsens joint-level pathogenesis in a male rat model of chronic knee osteoarthritis.

Objective: Low vagal tone is common in osteoarthritis (OA) comorbidities and results in greater peripheral inflammation. Characterizing vagal tone's role in OA pathogenesis may offer insights into OA's influences beyond the articular joint. We hypothesized that low vagal tone would accelerate onset of OA-related gait changes and worsen joint damage in a rat knee OA model. Methods: Knee OA was induced in male Sprague Dawley rats by transecting the medial collateral ligament and medial meniscus. Then, left cervical vagus nerve transection (VGX, n â€‹= â€‹9) or sham VGX (non-VGX, n â€‹= â€‹6) was performed. Gait and tactile sensitivity were assessed at baseline and across 12 weeks, with histology and systemic inflammation evaluated at endpoint. Results: At week 4, VGX animals showed limping gait characteristics through shifted stance times from their OA to non-OA limb (p â€‹= â€‹0.055; stance time imbalance â€‹= â€‹1.6 â€‹± â€‹1.6%) and shifted foot strike locations (p â€‹< â€‹0.001; spatial symmetry â€‹= â€‹48.4 â€‹± â€‹0.835%), while non-VGX animals walked with a balanced and symmetric gait. Also at week 4, while VGX animals had a mechanical sensitivity (50% withdrawal threshold) of 13.97 â€‹± â€‹7.70 compared to the non-VGX animal sensitivity of 29.74 â€‹± â€‹9.43, this difference was not statistically significant. Histologically, VGX animals showed thinner tibial cartilage and greater subchondral bone area than non-VGX animals (p â€‹= â€‹0.076; VGX: 0.80 â€‹± â€‹0.036 â€‹mm2; non-VGX: 0.736 â€‹± â€‹0.066 â€‹mm2). No group differences in systemic inflammation were observed at endpoint. Conclusions: VGX resulted in quicker onset of OA-related symptoms but remained unchanged at later timepoints. VGX also had thinner cartilage and abnormal bone remodeling than non-VGX. Overall, low vagal tone had mild effects on OA symptoms and joint remodeling, and not at the level seen in common OA comorbidities.

Hypertension contributes to exacerbated osteoarthritis pathophysiology in rats in a sex-dependent manner.

BACKGROUND: Hypertension is a common comorbidity of osteoarthritis (OA) with known autonomic dysregulation; thus, the autonomic nervous system may provide a shared underlying mechanism. The objective of this study was to examine the role of the autonomic nervous system in a preclinical model of OA and hypertension. METHODS: Experiments were conducted in spontaneously hypertensive rats and a normotensive control strain, including male and female rats. OA was surgically induced via medial meniscus transection with skin incision used as a sham control (n = 7-8/strain/sex/surgery). Tactile sensitivity, anxiety-related behavior, and serum corticosterone were measured at baseline then bi-weekly across 8 weeks. At weeks 9-10, cardiovascular responses to a chemical vagal nerve agonist were determined to indirectly evaluate vagus nerve function. The joint structure was assessed via grading of histological sections. RESULTS: In males, OA resulted in thinner cartilage in both hypertensive (OA vs. non-OA p < 0.001) and normotensive (OA vs. non-OA p < 0.001). Only females with comorbid hypertension and OA displayed thinner cartilage (p = 0.013). Male hypertensive OA animals had increased calcified subchondral bone compared to normotensive OA animals (p = 0.043) while female hypertensive OA animals had increased calcified subchondral bone compared to hypertensive sham animals (p < 0.001). All MCLT+MMT groups developed low-grade synovitis; interestingly, hypertensive OA females had higher synovitis scores than normotensive OA females (p = 0.046). Additionally, hypertension led to larger drops in blood pressure with vagal activation in both OA (hypertensive vs. normotensive p = 0.018) and sham (hypertensive vs. normotensive p < 0.001) male animals. In females, this trend held true only in OA animals (normotensive vs. hypertensive p = 0.005). CONCLUSION: These data provide preliminary evidence that hypertension influences OA progression and encourages further study into the autonomic nervous system as a possible mechanism.

Neuromodulation as a Potential Disease-Modifying Therapy for Osteoarthritis.

PURPOSE OF REVIEW: The following review discusses the therapeutic potential of targeting the autonomic nervous system (ANS) for osteoarthritis (OA) treatment and encourages the field to consider the candidacy of bioelectronic medicine as a novel OA treatment strategy. RECENT FINDINGS: The study of OA pathogenesis has focused on changes occurring at the joint level. As such, treatments for OA have been aimed at the local joint environment, intending to resolve local inflammation and decrease pain. However, OA pathogenesis has shown to be more than joint wear and tear. Specifically, OA-related peripheral and central sensitization can prompt neuroplastic changes in the nervous system beyond the articular joint. These neuroplastic changes may alter physiologic systems, like the neuroimmune axis. In this way, OA and related comorbidities may share roots in the form of altered neuroimmune communication and autonomic dysfunction. ANS modulation may be able to modify OA pathogenesis or reduce the impact of OA comorbidities. Moreover, blocking chronic nociceptive drive from the joint may help to prevent maladaptive nervous system plasticity in OA.

Autonomic Nervous System Dysregulation and Osteoarthritis Pain: Mechanisms, Measurement, and Future Outlook.

PURPOSE OF REVIEW: The autonomic nervous system is an important regulator of stress responses and exhibits functional changes in chronic pain states. This review discusses potential overlap among autonomic dysregulation, osteoarthritis (OA) progression, and chronic pain. From this foundation, we then discuss preclinical to clinical research opportunities to close gaps in our knowledge of autonomic dysregulation and OA. Finally, we consider the potential to generate new therapies for OA pain via modulation of the autonomic nervous system. RECENT FINDINGS: Recent reviews provide a framework for the autonomic nervous system in OA progression; however, research is still limited on the topic. In other chronic pain states, functional overlaps between the central autonomic network and pain processing centers in the brain suggest relationships between concomitant dysregulation of the two systems. Non-pharmacological therapeutics, such as vagus nerve stimulation, mindfulness-based meditation, and exercise, have shown promise in alleviating painful symptoms of joint diseases, and these interventions may be partially mediated through the autonomic nervous system. The autonomic nervous system appears to be dysregulated in OA progression, and further research on rebalancing autonomic function may lead to novel therapeutic strategies for treating OA pain.

Post-exercise heart rate recovery and its speed are associated with cardiac autonomic responsiveness following orthostatic stress test in men.

Objective: The present study sought to expand upon prior investigations of the relationship between the post-exercise heart rate recovery (HRR) and the cardiac autonomic responsiveness after orthostatic stress test.Method: HRR at the 1st, 3rd, and 5th min after maximal exercise test were correlated with relative change (Δ%) of time-domain (CV, pNN50, and rMSSD) and frequency-domain (TP, LF, HF, and LF/HF ratio) indices of heart rate variability (HRV) after active orthostatic test in 46 healthy men. Statistical analysis employed non-parametric tests with a p-value set at 5%.Results: HRR at 1st min correlated with Δ%pNN50 (rs:0.36 - p = .02). In the 3rd and 5th min, these measures correlated with Δ%pNN50, Δ%rMSSD, Δ%CV, Δ%TP, and Δ%HF indices (rs:0.33, 0.59 - p ≤ .05). Coefficient of HRR at the 1st min correlated with Δ%pNN50, Δ%rMSSD, and Δ%HF (rs:0.28, 0.45 - p ≤ .05). The 3rd and 5th min showed correlation with Δ%pNN50, Δ%rMSSD, Δ%HF, Δ%CV, and Δ%TP (rs:0.37, 0.64 - p ≤ .05). No correlation was found with indices combined sympathetic-parasympathetic modulation and HRR. After the sample was divided into high and low parasympathetic responsiveness subgroups after the orthostatic test, faster HRR was associated with the degree of parasympathetic responsiveness (reduction) following postural change (p ≤ .05).Conclusion: HRR throughout the 1st to 5th min is positively correlated with parasympathetic responsiveness and overall cardiac autonomic modulation of HRV after the orthostatic stress test, and faster HRR is positively correlated with the relative degree of parasympathetic responsiveness after the active postural change at rest in healthy men.

Cardiac Autonomic Function in the First Hours of Postnatal Life: An Observational Cross-Sectional Study in Term Neonates.

The aim of this study was to evaluate heart rate variability (HRV) within the first hours of extrauterine life in term neonates. HRV at 2-h and 14-h postpartum were compared by means of time domains (iRR, SDNN, and rMSSD); frequency domains (TP, LF, HF, and LF/HF ratio); and Poincare's Plot (SD1 and SD2) indices of HRV in 27 healthy, male, term newborns (NBs) born of elective cesarean delivery. Within 14 h after birth, the mean of the iRRs increased (Δ% = 4.4, p < 0.001) as well as parasympathetic indices (rMSSD: Δ% = 32.6; p < 0.03; HF: Δ% = 43.6; p < 0.00; SD1: Δ% = 32.6, p < 0.03). Respiratory rate (RR) decreased (RR: 2 h = 48 (43-55) cycle/min vs. 14 h = 45 (40-48) cycle/min p < 0.01). We concluded that within the first 14 h of birth, cardiac autonomic adjustments are characterized by an increase in parasympathetic activity. Concurrently, there were no significant changes observed in all other HRV indices in healthy, male, term neonates, and born of elective cesarean delivery.