Women have a greater cardiac vagal withdrawal to heat stress compared to men.

The heated environment shifts the sympatho-vagal balance toward sympathetic predominance and vagal withdrawal. Women's heart is more reliant on vagal autonomic control, while men's heart is more dependent on sympathetic control. However, sex differences in cardiovascular autonomic responses to heat stress remain unknown. We aimed to investigate the cardiovascular autonomic regulation under heat stress between sexes. Thirty-two young participants (27 ± 4 years old; 16 women) were enrolled in a single visit, resting for 30min at baseline (thermal reference condition TC; ∼24°C) and 30min under a heated environment (HOT; ∼38°C). Blood pressure (BP), skin temperature, electrocardiogram, and respiratory oscillations were continuously recorded. The heart rate variability (HRV) was assessed by spectral analysis (low-frequency [LFnu; sympathetic and vagal] and high-frequency [HFnu; vagal]), and symbolic analysis (0 V% [sympathetic] and 2UV%, and 2LV% [vagal]). The spontaneous baroreflex sensitivity (BRS) was calculated by the gain between BP and R-R within the LF band (αLF). The estimated maximal aerobic capacity and body surface area were employed as covariates in sex comparisons. The effects of HOT were the following: 1) Women have a greater cardiac vagal withdrawal to heat stress compared to men; 2) Sex differences on cardiac autonomic response to heat stress exist after controlling for the effect of estimated physical fitness and body surface area. Therefore, heat stress provokes a higher vagal withdrawal to the heart in women compared to men. It could be attributed to sex per se since significant differences between men and women were not modified after covariate analysis.

Reactome pathway analysis from whole-blood transcriptome reveals unique characteristics of systemic sclerosis patients at the preclinical stage.

Objective: This study aims to characterize differential expressed pathways (DEP) in subjects with preclinical systemic sclerosis (PreSSc) characterized uniquely by Raynaud phenomenon, specific autoantibodies, and/or capillaroscopy positive for scleroderma pattern. Methods: Whole-blood samples from 33 PreSSc with clinical prospective data (baseline and after 4 years of follow-up) and 16 matched healthy controls (HC) were analyzed for global gene expression transcriptome analysis via RNA sequencing. Functional Analysis of Individual Microarray Expression method annotated Reactome individualized pathways. ANOVA analysis identified DEP whose predictive capability were tested in logistic regression models after extensive internal validation. Results: At 4 years, 42.4% subjects progressed (evolving PreSSc), while the others kept stable PreSSc clinical features (stable PreSSc). At baseline, out of 831 pathways, 541 DEP were significant at a false discovery rate <0.05, differentiating PreSSc versus HC with an AUROC = 0.792 ± 0.242 in regression models. Four clinical groups were identified via unsupervised clustering (HC, HC and PreSSc with HC-like features, PreSSc and HC with PreSSc-like features, and PreSSc). Biological signatures changed with disease progression while remaining unchanged in stable subjects. The magnitude of change was related to the baseline cluster, yet no DEP at baseline was predictive of progression. Disease progression was mostly related to changes in signal transduction pathways especially linked to calcium-related events and inositol 1,4,5-triphosphate metabolism. Conclusion: PreSSc had distinguished Reactome pathway signatures compared to HC. Progression to definite SSc was characterized by a shift in biological fingertips. Calcium-related events promoting endothelial damage and vasculopathy may be relevant to disease progression.

Efficacy and Safety of Anti-SARS-CoV-2 Antiviral Agents and Monoclonal Antibodies in Patients with SLE: A Case-Control Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease (COVID-19) has spread pandemically with high rates of morbidity and mortality. COVID-19 has also posed unprecedented challenges in terms of rapid development of pharmacological countermeasures to prevent or contrast SARS-CoV-2 pathogenicity. Anti-SARS-CoV-2 antiviral agents and monoclonal antibodies have been specifically designed to attenuate COVID-19 morbidity and prevent mortality in vulnerable subjects, such as patients with immune-mediated diseases, but evidence for the safe and effective use of these drugs in this latter population group is scarce. Therefore, we designed a retrospective, multicentre, observational, case-control study to analyse the impact of these treatments in COVID-19 patients with systemic lupus erythematosus (SLE), a paradigmatic, multi-organ autoimmune disease. We identified 21 subjects treated with antivirals and/or monoclonal antibodies who were matched with 42 untreated patients by age, sex, SLE extension and duration. Treated patients had higher baseline SLE disease activity index 2000 scores [SLEDAI-2K median (interquartile range) = 4 (1-5) vs. 0 (0-2); p = 0.009], higher prednisone doses [5 (0-10) mg vs. 0 (0-3) mg; p = 0.002], and more severe COVID-19 symptoms by a five-point World Health Organisation-endorsed analogue scale [1 (0-1) vs. 0 (0-1); p < 0.010] compared to untreated patients. There was no difference between groups in terms of COVID-19 outcomes and sequelae, nor in terms of post-COVID-19 SLE exacerbations. Three subjects reported mild adverse events (two with monoclonal antibodies, one with nirmatrelvir/ritonavir). These data suggest that anti-SARS-CoV-2 antivirals and monoclonal antibodies might be safely and effectively used in patients with SLE, especially with active disease and more severe COVID-19 symptoms at presentation.

Systemic sclerosis and primary biliary cholangitis: Longitudinal data to determine the outcomes.

Background: Several studies described the cross-sectional characteristics of systemic sclerosis patients and coexisting primary biliary cholangitis, but longitudinal prognostic data are lacking. Aims: To describe the systemic sclerosis-primary biliary cholangitis phenotype, including baseline characteristics and outcomes. Methods: We performed a multicentre the European Scleroderma Trials and Research Group study of systemic sclerosis patients with primary biliary cholangitis or with primary biliary cholangitis-specific antibodies, matched with systemic sclerosis controls free from hepatobiliary involvement matched for disease duration and cutaneous subset. Data were recorded at baseline and at the last available visit. Results: A total of 261 patients were enrolled (115 primary biliary cholangitis-systemic sclerosis, 161 systemic sclerosis). At baseline, systemic sclerosis-primary biliary cholangitis patients had a higher prevalence of anti-centromere antibodies (p = 0.0023) and a lower prevalence of complete absence of digital ulcers. The milder vascular involvement was confirmed at follow-up when crucial differences emerged in the percentage of patients experiencing digital ulcers; a significantly higher number of patients who never experienced digital ulcers were observed among primary biliary cholangitis-systemic sclerosis patients (p = 0.0015). Moreover, a greater incidence of pulmonary arterial hypertension (p < 0.001) and of conduction blocks (p = 0.0256) was observed in systemic sclerosis patients without primary biliary cholangitis. Patients with primary biliary cholangitis had higher levels of liver enzymes at baseline than systemic sclerosis patients; a significant decrease in liver enzymes was observed at follow-up. Out of 18 patients with cholangitis, one received a liver transplant at follow-up. Conclusion: Our data show that systemic sclerosis-primary biliary cholangitis exhibit a mild systemic sclerosis and primary biliary cholangitis phenotype with outcomes being in general favourable.

Transcutaneous auricular branch vagal nerve stimulation as a non-invasive add-on therapeutic approach for pain in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease with health-related quality of life (HRQoL) high impairment. Pain is of paramount importance to be targeted by therapeutical approaches. Our study aim was to perform an add-on device-based non-invasive neuromodulatory treatment through transcutaneous auricular vagal nerve stimulation (tVNS) in patients with SSc, assessing its effects on pain as primary endpoint and on inflammation, cardiovascular autonomic control and HRQoL. METHODS: Thirty-two patients with SSc were enrolled based on reported pain assessed through Numeric Rating Scale (NRS). Twenty-one (90% with limited cutaneous SSc) completed a randomised, cross-over, patient-blind trial, in which interventional and active control were used in random order for 4 weeks, interspersed with 4 weeks washout. NRS, Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) Item4 for pain interference, heart rate variability (HRV), serum cytokines and HRQoL questionnaires (Health Assessment Questionnaire, Patient Health Questionnaire-9, University of California, Los Angeles Gastrointestinal Tract, Pittsburgh Sleep Quality Index) were assessed at baseline, at T1 (after 1 month of tVNS or active control), at T2 (after washout) and at T3 (after 1 month of active control or tVNS). T-test for paired data and Wilcoxon signed-rank test for non-normally distributed parameters were performed to compare the effect of tVNS and active control. RESULTS: NRS pain was significantly reduced by tVNS and not by active control (Mean±SD: -27.7%±21.3% vs -7.7%±26.3%, p=0.002). Interleukin-6 was downregulated in tVNS versus active control (p=0.029). No significant differences were observed in tVNS versus active control for PROMIS-29 Item4, QoL scales and HRV with both spectral and symbolic analyses. CONCLUSION: tVNS demonstrated to be a safe and non-invasive add-on tool to reduce pain in SSc.

Social Isolation: A Narrative Review on the Dangerous Liaison between the Autonomic Nervous System and Inflammation.

Social isolation and feelings of loneliness are related to higher mortality and morbidity. Evidence from studies conducted during space missions, in space analogs, and during the COVID-19 pandemic underline the possible role of the autonomic nervous system in mediating this relation. Indeed, the activation of the sympathetic branch of the autonomic nervous system enhances the cardiovascular response and activates the transcription of pro-inflammatory genes, which leads to a stimulation of inflammatory activation. This response is adaptive in the short term, in that it allows one to cope with a situation perceived as a threat, but in the long term it has detrimental effects on mental and physical health, leading to mood deflection and an increased risk of cardiovascular disease, as well as imbalances in immune system activation. The aim of this narrative review is to present the contributions from space studies and insights from the lockdown period on the relationship between social isolation and autonomic nervous system activation, focusing on cardiovascular impairment and immune imbalance. Knowing the pathophysiological mechanisms underlying this relationship is important as it enables us to structure effective countermeasures for the new challenges that lie ahead: the lengthening of space missions and Mars exploration, the specter of future pandemics, and the aging of the population.

Proteomic aptamer analysis reveals serum markers that characterize preclinical systemic sclerosis (SSc) patients at risk for progression toward definite SSc.

BACKGROUND: The study of molecular mechanisms characterizing disease progression may be relevant to get insights into systemic sclerosis (SSc) pathogenesis and to intercept patients at very early stage. We aimed at investigating the proteomic profile of preclinical systemic sclerosis (PreSSc) via a discovery/validation two-step approach. METHODS: SOMAcan aptamer-based analysis was performed on a serum sample of 13 PreSSc (discovery cohort) according to 2001 LeRoy and Medsger criteria (characterized solely by Raynaud phenomenon plus a positive nailfold capillaroscopy and SSc-specific antibodies without any other sign of definite disease) and 8 healthy controls (HCs) age, gender, and ethnicity matched. Prospective data were available up to 4±0.6 years to determine the progression to definite SSc according to the EULAR/ACR 2013 classification criteria. In proteins with relative fluorescence units (RFU) > |1.5|-fold vs HCs values, univariate analysis was conducted via bootstrap aggregating models to determine the predicting accuracy (progression vs non-progression) of categorized baseline protein values. Gene Ontologies (GO terms) and Reactome terms of significant proteins at the adjusted 0.05 threshold were explored. Significant proteins from the discovery cohort were finally validated via ELISAs in an independent validation cohort of 50 PreSSc with clinical prospective data up to 5 years. Time-to-event analysis for interval-censored data was used to evaluate disease progression. RESULTS: In the discovery cohort, 286 out of 1306 proteins analyzed via SomaScan, were differentially expressed versus HCs. Ten proteins were significantly associated with disease progression; analysis through GO and Reactome showed differentially enriched pathways involving angiogenesis, endothelial cell chemotaxis, and endothelial cell chemotaxis to fibroblast growth factor (FGF). In the validation cohort, endostatin (HR=10.23, CI95=2.2-47.59, p=0.003) was strongly associated with disease progression, as well as bFGF (HR=0.84, CI95=0.709-0.996, p=0.045) and PAF-AHß (HR=0.372, CI95=0.171-0.809, p=0.013) CONCLUSIONS: A distinct protein profile characterized PreSSc from HCs and proteins associated with hypoxia, vasculopathy, and fibrosis regulation are linked with the progression from preclinical to definite SSc. These proteins, in particular endostatin, can be regarded both as markers of severity and molecules with pathogenetic significance as well as therapeutic targets.

Longitudinal global transcriptomic profiling of preclinical systemic sclerosis reveals molecular changes associated with disease progression.

OBJECTIVE: To investigate peripheral blood cell (PBCs) global gene expression profile of SSc at its preclinical stage (PreSSc) and to characterize the molecular changes associated with progression to a definite disease over time. MATERIAL AND METHODS: Clinical data and PBCs of 33 participants with PreSSc and 16 healthy controls (HCs) were collected at baseline and follow-up (mean 4.2 years). Global gene expression profiling was conducted by RNA sequencing and a modular analysis was performed. RESULTS: Comparison of baseline PreSSc to HCs revealed 2889 differentially expressed genes. Interferon signalling was the only activated pathway among top over-represented pathways. Moreover, 10 modules were significantly decreased in PreSSc samples (related to lymphoid lineage, cytotoxic/NK cell, and erythropoiesis) in comparison to HCs. At follow-up, 14 subjects (42.4%) presented signs of progression (evolving PreSSc) and 19 remained in stable preclinical stage (stable PreSSc). Progression was not associated with baseline clinical features or baseline PBC transcript modules. At follow-up stable PreSSc normalized their down-regulated cytotoxic/NK cell and protein synthesis modules while evolving PreSSc kept a down-regulation of cytotoxic/NK cell and protein synthesis modules. Transcript level changes of follow-up vs baseline in stable PreSSc vs evolving PreSSc showed 549 differentially expressed transcripts (336 up and 213 down) with upregulation of the EIF2 Signalling pathway. CONCLUSIONS: Participants with PreSSc had a distinct gene expression profile indicating that molecular differences at a transcriptomic level are already present in the preclinical stages of SSc. Furthermore, a reduced NK signature in PBCs was related to SSc progression over time.

Remdesivir-induced bradycardia in patients hospitalized with SARS-CoV2 infection: a possible vagally-mediated mechanism.

Recently, case series studies on patients with SARS-CoV-2 infection reported an association between remdesivir (RDV) administration and incidental bradycardia. However, the phenomenon has not yet been described in detail. We conducted a retrospective case-control study to evaluate the occurrence of RDV-related bradycardia in patients hospitalized for SARS-CoV2 pneumoniae. We retrospectively evaluated 71 patients, hospitalized in six internal medicine wards of the Milan area, affected by mild-to-moderate COVID-19 who received RDV (RDV group) and 54 controls, matched for sex, age and disease severity on admission (CTR group). The mean heart rate value recorded during the first two days of hospitalization was considered as baseline heart rate (HRb). Heart rate values relative to the 5-days treatment and the 5-days post-treatment were extracted for RDV group, while heart rate values relative to 10 days of hospitalization were considered for the CTR group. ΔHR values were calculated as maximum HR drop versus HRb. Possible associations between ΔHR and clinical-demographic factors were assessed through regression analysis. The RDV group experienced a significantly higher incidence of bradycardia compared to the CTR group (56% vs 33%, OR 2.6, 95% CI 1.2-5.4, p value = 0.011). Moreover, the RDV group showed higher ΔHR values than the CTR group. The HR progressively decreased with daily administration of RDV, reaching the maximun drop on day six (-8.6±1.9 bpm). In RDV group, patients who experienced bradycardia had higher drop in HR, higher alanine aminotransferase (ALT) values at the baseline (bALT) and during the RDV administration period. ΔHR was positively associated with HRb (ß = 0.772, p < 0.001) and bALT (ß = 0.245, p = 0.005). In conclusion, our results confirmed a significant association between RDV administration and development of bradycardia. This effect was proportional to baseline HR and was associated with higher levels of baseline ALT, suggesting a possible interaction between RDV liver metabolism and a vagally-mediated effect on HR due to increased availability of RDV metabolites.

Cardiovascular autonomic modulation during passive heating protocols: a systematic review.

Objective.To conduct a systematic review of the possible effects of passive heating protocols on cardiovascular autonomic control in healthy individuals.Approach.The studies were obtained from MEDLINE (PubMed), LILACS (BVS), EUROPE PMC (PMC), and SCOPUS databases, simultaneously. Studies were considered eligible if they employed passive heating protocols and investigated cardiovascular autonomic control by spontaneous methods, such as heart rate variability (HRV), systolic blood pressure variability (SBPV), and baroreflex sensitivity (BRS), in healthy adults. The revised Cochrane risk-of-bias tool (RoB-2) was used to assess the risk of bias in each study.Main results.Twenty-seven studies were included in the qualitative synthesis. Whole-body heating protocols caused a reduction in cardiac vagal modulation in 14 studies, and two studies reported both increased sympathetic modulation and vagal withdrawal. Contrariwise, local-heating protocols and sauna bathing seem to increase cardiac vagal modulation. A reduction of BRS was reported in most of the studies that used whole-body heating protocols. However, heating effects on BRS remain controversial due to methodological differences among baroreflex analysis and heating protocols.Significance.Whole-body heat stress may increase sympathetic and reduce vagal modulation to the heart in healthy adults. On the other hand, local-heating therapy and sauna bathing seem to increase cardiac vagal modulation, opposing sympathetic modulation. Nonetheless, further studies should investigate acute and chronic effects of thermal therapy on cardiovascular autonomic control.

Predicting the Progression of Very Early Systemic Sclerosis: Current Insights.

Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease with distinct pathological hallmarks (ie, inflammation, vasculopathy, fibrosis) that may predominate at different stages in the disease course with varying severity. Initial efforts to classify patients with SSc identified a subset of patients with very early SSc. These patients possessed signs of SSc (eg, Raynaud phenomenon, SSc specific autoantibodies and/or nailfold capillary abnormalities) without fulfilling complete SSc classification criteria. Recognizing the inherent value in early diagnosis and intervention in SSc, researchers have endeavored to identify risk factors for progression from very early SSc to definite SSc. The present review summarizes the clinical phenotype of patients with very early and early SSc. Through a scoping review of recent literature, this review also describes risk factors for progression to definite SSc with a focus on the specific clinical features that arise early in the SSc disease course (eg, diffuse cutaneous sclerosis, interstitial lung disease, esophageal dysfunction, renal crisis, cardiac involvement). In addition to clinical risk factors, this review provides evidence for how biological data (ie, serological, genomic, proteomic profiles, skin bioengineering methods) can be integrated into risk assessment models in the future. Furthering our understanding of biological features of very early SSc will undoubtedly provide novel insights into SSc pathogenesis and may illuminate new therapeutic targets to prevent progression of SSc.

The Systolic Pulmonary Arterial Pressure Liaises Impaired Cardiac Autonomic Control to Pro-inflammatory Status in Systemic Sclerosis Patients.

The current study was undertaken to test the hypothesis that systemic sclerosis (SSc) patients with higher systolic pulmonary arterial pressures (PAPs) present a blunted cardiac autonomic modulation and a pro-inflammatory profile. Thirty-nine SSc patients were enrolled (mean age 57 ± 11 years). ECG and respiration were recorded in the supine (SUP) position and during the active standing (ORT). Heart rate variability (HRV) analysis was performed on samples of 300 beats. The symbolic analysis identified three patterns, 0V%, (sympathetic) and 2UV% and 2LV%, (vagal). The %ΔORT was calculated from the differences between HRV in ORT and SUP, normalized (%) by the HRV values at rest. The PAPs was obtained non-invasively through echocardiography. For the inter-group analysis, participants were allocated in groups with higher (+PAPs ≥ median) and lower PAPs (-PAPs < median) values. At rest, the cardiac sympathetic modulation (represented by 0V%) was positively correlated with PAPs, while parasympathetic modulation (represented by 2LV%) was negatively correlated with PAPs. The dynamic response to ORT (represented by Δ0V% and Δ2LV%), sympathetic and parasympathetic were negatively and positively correlated with PAPs, respectively. The +PAPs group presented a higher inflammatory status and a blunted cardiac autonomic response to ORT (↓Δ0V% and ↑Δ2LV%) compared to the -PAPs group. These findings suggest an interplay among cardiac autonomic control, inflammatory status, and cardiopulmonary mechanics that should be considered for the assessment, monitoring, and treatment of SSc patients.

Long-Term Clinical Outcome in Systemic Lupus Erythematosus Patients Followed for More Than 20 Years: The Milan Systemic Lupus Erythematosus Consortium (SMiLE) Cohort.

Tackling active disease to prevent damage accrual constitutes a major goal in the management of patients with systemic lupus erythematosus (SLE). Patients with early onset disease or in the early phase of the disease course are at increased risk of developing severe manifestations and subsequent damage accrual, while less is known about the course of the disease in the long term. To address this issue, we performed a multicentre retrospective observational study focused on patients living with SLE for at least 20 years and determined their disease status at 15 and 20 years after onset and at their last clinical evaluation. Disease activity was measured through the British Isles Lupus Assessment Group (BILAG) tool and late flares were defined as worsening in one or more BILAG domains after 20 years of disease. Remission was classified according to attainment of lupus low-disease-activity state (LLDAS) criteria or the Definitions Of Remission In SLE (DORIS) parameters. Damage was quantitated through the Systemic Lupus Erythematosus International Collaborating Clinics/American College of Rheumatology damage index (SLICC/ACR-DI). LLAS/DORIS remission prevalence steadily increased over time. In total, 84 patients had a late flare and 88 had late damage accrual. Lack of LLDAS/DORIS remission status at the 20 year timepoint (p = 0.0026 and p = 0.0337, respectively), prednisone dose ≥ 7.5 mg (p = 9.17 × 10-5) or active serology (either dsDNA binding, low complement or both; p = 0.001) were all associated with increased late flare risk. Late flares, in turn, heralded the development of late damage (p = 2.7 × 10-5). These data suggest that patients with longstanding SLE are frequently in remission but still at risk of disease flares and eventual damage accrual, suggesting the need for tailored monitoring and therapeutic approaches aiming at effective immunomodulation besides immunosuppression, at least by means of steroids.

The Impact of Anti-SARS-CoV-2 Vaccine in Patients with Systemic Lupus Erythematosus: A Multicentre Cohort Study.

Vulnerable subjects, including systemic lupus erythematosus (SLE) patients, have been prioritised to receive anti-SARS-CoV-2 vaccines. Few data about the safety of these vaccines in SLE are available. The aim of our study is to investigate the safety of anti-SARS-CoV-2 vaccines in SLE. We included 452 SLE patients, referring to seven tertiary centres, who were immunised. A total of 119 (26%) reported side effects (SE) after the first and/or the second shot (the most frequent SE were fever, local reaction, fatigue, and arthralgia). Patients with constitutional symptoms and those on an immunosuppressive regimen (especially belimumab) showed more SE. In addition, 19 (4%) had a flare after the immunisation (flares classified by organ involvement: six musculoskeletal with constitutional symptoms, four renal, three cardio-respiratory, three haematological, two mucocutaneous). None of the patients needed hospitalisation and none died. Moreover, 15 required a transient increase in corticosteroids and four were treated with steroid pulses. One patient required an additional rituximab course. Anti-dsDNA, moderate/high DAS before vaccine, and belimumab were found more frequently in patients with disease flare. Anti-SARS-CoV-2 vaccines are safe in SLE patients, and they should be recommended in these patients, as the potential benefits widely outweigh the risk of SE. Treatment adjustment might be considered with the aim of minimising SE risk and flare.

Dysautonomia in Parkinson's Disease: Impact of Glucocerebrosidase Gene Mutations on Cardiovascular Autonomic Control.

Evidence from clinical practice suggests that PD patients with the Glucocerebrosidase gene mutations (GBA-PD) are characterized by more severe dysautonomic symptoms than patients with idiopathic PD (iPD). Therefore, an accurate assessment of cardiovascular autonomic control (CAC) is necessary to clarify the role of GBA mutations in the pathophysiology of PD. We evaluated the CAC at rest and during orthostatic challenge of 15 iPD, 15 GBA-PD and 15 healthy controls (CTR). ECG and respiration were recorded in supine position and during active standing. The analysis of Heart Rate Variability (HRV) was performed on ECG recordings using two different approaches, linear spectral analysis and non-linear symbolic analysis. GBA-PD patients presented more frequently an akinetic-rigid phenotype and cognitive dysfunction than iPD patients. Both iPD and GBA-PD group were characterized by a lower spectral HRV than CTR group. At rest, the GBA-PD group was characterized by a lower parasympathetic modulation and a shift of the sympathovagal balance toward a sympathetic predominance compared to the CTR group. Moreover, the GBA-PD patients presented a lower HR increment and a lower or absent reduction of the vagal modulation in response to the active standing than iPD patients. Lastly, the cardiovascular autonomic dysfunction in PD patients was associated with longer disease duration, and with the occurrence of REM sleep behavior disorder and constipation. Our findings suggest a more severe impairment of the CAC in PD patients with GBA mutations. These results and further studies on the role of GBA mutations could allow a stratification based on cardiovascular risk in PD patients and the implementation of specific prevention programs.

The Interplay between Autonomic Nervous System and Inflammation across Systemic Autoimmune Diseases.

The autonomic nervous system (ANS) and the immune system are deeply interrelated. The ANS regulates both innate and adaptive immunity through the sympathetic and parasympathetic branches, and an imbalance in this system can determine an altered inflammatory response as typically observed in chronic conditions such as systemic autoimmune diseases. Rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis all show a dysfunction of the ANS that is mutually related to the increase in inflammation and cardiovascular risk. Moreover, an interaction between ANS and the gut microbiota has direct effects on inflammation homeostasis. Recently vagal stimulation techniques have emerged as an unprecedented possibility to reduce ANS dysfunction, especially in chronic diseases characterized by pain and a decreased quality of life as well as in chronic inflammation.

Sjögren's syndrome and other rare and complex connective tissue diseases: an intriguing liaison.

Sjögren's syndrome (SS) is a systemic autoimmune disease that frequently occurs concomitantly with other systemic connective tissue disorders, including rare and complex diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The presence of SS influences the clinical expression of the other autoimmune diseases, thus offering the unique opportunity to explore the similarities in genetic signatures, as well as common environmental and biologic factors modulating the expression of disease phenotypes. In this review, we will specifically discuss the possibility of defining "SS/SLE" and "SS/SSc" as distinct subsets within the context of connective tissue diseases with different clinical expression and outcomes, thus deserving an individualised assessment and personalised medical interventions.

Sympatho-Vagal Dysfunction in Systemic Sclerosis: A Follow-Up Study.

Systemic sclerosis (SSc) patients often present cardiovascular autonomic dysfunction, which is associated with the risk of arrhythmic complications and mortality. However, little is known regarding the progression of cardiac autonomic impairment over time. We aimed to evaluate the cardiac autonomic modulation among SSc with limited cutaneous (lcSSc), diffuse cutaneous (dcSSc) subset, and age-matched healthy control (HC) at baseline (t0) and five-year follow-up (t1). In this follow-up study, ECG was recorded at t0 and t1 in twenty-four SSc patients (dcSSc; n = 11 and lcSSc; n = 13) and 11 HC. The heart rate variability (HRV) analysis was conducted. The spectral analysis identified two oscillatory components, low frequency (LF) and high frequency (HF), and the sympatho-vagal balance was assessed by the LF/HF ratio. The LF/HF increased (p = 0.03), and HF reduced at t1 compared to t0 in dcSSc (p = 0.03), which did not occur in the lcSSc and HC groups. Otherwise, both lcSSc and dcSSc groups presented augmented LF/HF at t0 and t1 compared to HC (p < 0.01). In conclusion, a worsening of cardiac autonomic dysfunction is related to the dcSSc subset, in which a more extent of skin fibrosis and internal organs fibrosis is present.