Distinctive clinical traits of lupus-related myocarditis: a multicentre retrospective study.

OBJECTIVES: Cardiovascular involvement in systemic lupus erythematosus (SLE) is frequent but little is known about possible distinctive traits of SLE-related myocarditis (myoSLE) in comparison to patients with SLE (onlySLE) or myocarditis alone (onlyMyo). METHODS: A retrospective analysis was performed comparing patients with myoSLE (n = 25) from three centres with consecutive patients with onlySLE (n = 279) and onlyMyo (n = 88). SLE patients were dichotomised by disease duration ≤1 vs >1 year into recent onlySLE/early myoSLE vs longstanding onlySLE/late myoSLE. Further stratification into disease duration of 1-5, 5-10 and >10 years was also performed. SLE disease activity index 2000 (SLEDAI-2K) was used to estimate disease activity. Myocarditis was diagnosed through biopsy or magnetic resonance. RESULTS: Women were significantly more frequent among myoSLE than among onlyMyo (72% vs 43%; p= 0.013). Compared with onlyMyo, myoSLE patients had a higher frequency of conduction abnormalities (22% vs 5%; p= 0.046) and presented with numerically higher frequencies of left ventricular function compromise (48% vs 30%), along with higher pro-brain natriuretic peptide levels. Inflammation markers were higher in myoSLE compared with onlyMyo and to patients with onlySLE with >10 years of disease duration. SLEDAI-2K was significantly higher in late myoSLE than in longstanding onlySLE. Antiphospholipid syndrome was more frequent in myoSLE than in onlySLE. Multivariate analysis showed an association among myoSLE, anti-beta-2-glycoprotein I antibodies (aB2GPI, p= 0.014) and a higher number of involved British Isles Lupus Assessment Group domains in patient history (p= 0.003). CONCLUSION: myoSLE has unique clinical traits compared with other forms of myocarditis and is associated with aB2GPI and a more severe SLE course.

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.

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.

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.

Impact of the COVID-19 pandemic in patients with systemic lupus erythematosus throughout one year.

Little is known about the impact of coronavirus disease 2019 (COVID-19) pandemic to the care of patients with systemic lupus erythematosus (SLE) in the long-term. By crossing population data with the results of a web-based survey focused on the timeframes January-April and May-December 2020, we found that among 334/518 responders, 28 had COVID-19 in 2020. Seventeen cases occurred in May-December, in parallel with trends in the general population and loosening of containment policy strength. Age > 40 years (p = 0.026), prednisone escalation (p = 0.008) and infected relatives (p < 0.001) were most significantly associated with COVID-19. Weaker associations were found with asthma, lymphadenopathy and azathioprine or cyclosporine treatment. Only 31% of patients with infected relatives developed COVID-19. Healthcare service disruptions were not associated with rising hospitalisations. Vaccination prospects were generally welcomed. Our data suggest that COVID-19 has a moderate impact on patients with SLE, which might be significantly modulated by public health policies, including vaccination.

Anti-RNPC-3 antibody predicts poor prognosis in patients with interstitial lung disease associated to systemic sclerosis.

OBJECTIVE: To analyse the prevalence, the clinical characteristics, the overall survival and the event-free survival (EFS) of SSc patients who express anti-U11/U12 RNP (RNPC-3) antibodies. METHODS: A total of 447 SSc patients from Barcelona (n = 286) and Milan (n = 161) were selected. All samples were tested using a particle-based multi-analyte technology. We compared anti-RNPC-3 positive and negative patients. Epidemiological, clinical features and survival were analysed. End-stage lung disease (ESLD) was defined if the patient developed forced vital capacity <50% of predicted, needed oxygen therapy or lung transplantation. EFS was defined as the period of time free of either ESLD or death. RESULTS: Nineteen of 447 (4.3%) patients had anti-RNPC-3 antibodies and interstitial lung disease (ILD) was more frequent (11, 57.9% vs 144, 33.6%, P =0.030) in individuals with anti-RNPC-3 antibodies. More patients reached ESLD in the positive group (7, 36.8% vs 74, 17.3%, P = 0.006), and a higher use of non-glucocorticoid immunosuppressive drugs was observed (11, 57.9% vs 130, 30.4%, P = 0.012). Anti-RNPC-3 positive patients had lower EFS, both in the total cohort (log-rank P =0.001), as well as in patients with ILD (log-rank P = 0.002). In multivariate Cox regression analysis, diffuse cutaneous subtype, age at onset, the presence of ILD or pulmonary arterial hypertension and the expression of anti-RNPC-3 positivity or anti-topo I were independently associated with worse EFS. CONCLUSION: The presence of anti-RNPC-3 was associated with higher frequency of ILD and either ESLD or death. These data suggest anti-RNPC-3 is an independent poor prognosis antibody in SSc, especially if ILD is also present.

Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients.

OBJECTIVES: The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations. METHODS: Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated. RESULTS: Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples. CONCLUSIONS: We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc.

Cardiopulmonary exercise testing in a combined screening approach to individuate pulmonary arterial hypertension in systemic sclerosis.

OBJECTIVES: The DETECT algorithm has been developed to identify SSc patients at risk for pulmonary arterial hypertension (PAH) yielding high sensitivity but low specificity, and positive predictive value. We tested whether cardiopulmonary exercise testing (CPET) could improve the performance of the DETECT screening strategy. METHODS: Consecutive SSc patients over a 30-month period were screened with the DETECT algorithm and positive subjects were referred for CPET before the execution of right-heart catheterization. The predictive performance of CPET on top of DETECT was evaluated and internally validated via bootstrap replicates. RESULTS: Out of 314 patients, 96 satisfied the DETECT application criteria and 54 were positive. PAH was ascertained in 17 (31.5%) and pre-capillary pulmonary hypertension in 23 (42.6%) patients. Within CPET variables, the slope of the minute ventilation to carbon dioxide production relationship (VE/VCO2 slope) had the best performance to predict PAH at right-heart catheterization [median (interquartile range) of specificity 0.778 (0.714-0.846), positive predictive value 0.636 (0.556-0.750)]; exploratory analysis on pre-capillary yielded a specificity of 0.714 (0.636-0.8) and positive predictive value of 0.714 (0.636-0.8). CONCLUSION: In association with the DETECT algorithm, CPET may be considered as a useful tool in the workup of SSc-related pulmonary hypertension. The sequential determination of the VE/VCO2 slope in DETECT-positive subjects may reduce the number of unnecessary invasive procedures without any loss in the capability to capture PAH. This strategy had also a remarkable performance in highlighting the presence of pre-capillary pulmonary hypertension.

Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures.

OBJECTIVE: In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study. METHODS: Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples. RESULTS: At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score. CONCLUSION: HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures.

Update on the Gastrointestinal Microbiome in Systemic Sclerosis.

PURPOSE OF REVIEW: Accumulating evidence suggests that gut microbiota affect the development and function of the immune system and may play a role in the pathogenesis of autoimmune diseases. The purpose of this review is to summarize recent studies reporting gastrointestinal microbiota aberrations associated with the systemic sclerosis disease state. RECENT FINDINGS: The studies described herein have identified common changes in gut microbial composition. Specifically, patients with SSc have decreased abundance of beneficial commensal genera (e.g., Faecalibacterium, Clostridium, and Bacteroides) and increased abundance of pathobiont genera (e.g., Fusobacterium, Prevotella, Erwinia). In addition, some studies have linked specific genera with the severity of gastrointestinal symptoms in systemic sclerosis. More research is needed to further characterize the gastrointestinal microbiota in systemic sclerosis and understand how microbiota perturbations can affect inflammation, fibrosis, and clinical outcomes. Interventional studies aimed at addressing/correcting these perturbations, either through dietary modification, pro/pre-biotic supplementation, or fecal transplantation, may lead to improved outcomes for patients with systemic sclerosis.

The magnitude of cytokine production by stimulated CD56+ cells is associated with early stages of systemic sclerosis.

Immune activation is a hallmark of systemic sclerosis (SSc). However, the immunological alterations that occur in preclinical and non-fibrotic SSc and that differentiate these subjects from those with primary Raynaud's phenomenon (PRP) or healthy controls (HC) are poorly defined. We isolated CD56+ (NK/NKT-like) cells from HC, patients with PRP, early SSc (EaSSc) and definite SSc without skin or lung fibrosis. Cytokine production upon different activating stimuli was measured via a multiplex immuno assay. Clearly discriminative patterns among the different stages of SSc were most markedly observed after TLR1/2 stimulation, with increased IL-6, TNF-α and MIP-1α/CCL3 production in definite SSc patients as compared to HC and/or PRP. Initial alterations were observed in EaSSc patients with an intermediate secretion pattern between HC/PRP and definite SSc. CD56+ cells from patients at different stages of SSc differentially respond to TLR stimulation, highlighting the relevance of natural immunity in the developmental and pre-fibrotic SSc.

Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway.

OBJECTIVES: TYK2 is a common genetic risk factor for several autoimmune diseases. This gene encodes a protein kinase involved in interleukin 12 (IL-12) pathway, which is a well-known player in the pathogenesis of systemic sclerosis (SSc). Therefore, we aimed to assess the possible role of this locus in SSc. METHODS: This study comprised a total of 7103 patients with SSc and 12 220 healthy controls of European ancestry from Spain, USA, Germany, the Netherlands, Italy and the UK. Four TYK2 single-nucleotide polymorphisms (V362F (rs2304256), P1104A (rs34536443), I684S (rs12720356) and A928V (rs35018800)) were selected for follow-up based on the results of an Immunochip screening phase of the locus. Association and dependence analyses were performed by the means of logistic regression and conditional logistic regression. Meta-analyses were performed using the inverse variance method. RESULTS: Genome-wide significance level was reached for TYK2 V362F common variant in our pooled analysis (p=3.08×10(-13), OR=0.83), while the association of P1104A, A928V and I684S rare and low-frequency missense variants remained significant with nominal signals (p=2.28×10(-3), OR=0.80; p=1.27×10(-3), OR=0.59; p=2.63×10(-5), OR=0.83, respectively). Interestingly, dependence and allelic combination analyses showed that the strong association observed for V362F with SSc, corresponded to a synthetic association dependent on the effect of the three previously mentioned TYK2 missense variants. CONCLUSIONS: We report for the first time the association of TYK2 with SSc and reinforce the relevance of the IL-12 pathway in SSc pathophysiology.

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.

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.

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.

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.

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.