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Background: Metabolic syndrome (MetS) is associated with an increased risk of cardiovascular diseases. Compelling evidence supports the key role of dysfunction in the autonomic nervous system in that association, as well as mutual correlation among the components of MetS. The autonomic nervous system index (ANSI) is a percentile-ranked unitary proxy of cardiac autonomic regulation (CAR) that is designed to be free of age and sex bias, with higher values indicating better autonomic control. This study investigates CAR using the ANSI in patients with MetS., Methods: A total of 133 patients referred to the Exercise Medicine Clinic of Istituto Auxologico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) underwent CAR assessment using the ANSI and answered lifestyle questions in ad hoc questionnaires. The participants were retrospectively subdivided into two groups according to the presence or absence of MetS criteria., Results: Of the subjects, 58 were diagnosed with MetS, and 75 were not (no MetS). The ANSI was significantly impaired (32.9 vs. 44.8, P <0.01) in the MetS group, and ANSI scores showed a decreasing trend ( P =0.004) as the number of MetS components increased. No significant lifestyle differences were found between the groups., Conclusion: The ANSI was significantly reduced in subjects with MetS, and, net of age and sex effects, CAR impairment became progressively more apparent as the number of MetS components increased.

Introduction: This review delves into Fibromyalgia Syndrome (FMS), a chronic pain condition demanding thorough understanding for precise diagnosis and treatment. Yet, a definitive pharmacological solution for FMS remains elusive., Areas Covered: In this article, we systematically analyze various pharmacotherapeutic prospects for FMS treatment, organized into sections based on the stage of drug development and approval. We begin with an overview of FDA-approved drugs, discussing their efficacy in FMS treatment. Next, we delve into other medications currently used for FMS but still undergoing further study, including opioids and muscle relaxants. Further, we evaluate the evidence behind medications that are currently under study, such as cannabinoids and naltrexone. Lastly, we explore new drugs that are in phase II trials. Our research involved a thorough search on PUBMED, Google Scholar, and clinicaltrials.gov. We also discuss the action mechanisms of these drugs and their potential use in specific patient groups., Expert Opinion: A focus on symptom-driven, combination therapy is crucial in managing FMS. There is also a need for ongoing research into drugs that target neuroinflammation, immunomodulation, and the endocannabinoid system. Bridging the gap between benchside research and clinical application is challenging, but it holds potential for more targeted and effective treatment strategies.

Objectives: To evaluate the role of exercise in the management of fibromyalgia syndrome (FM) by addressing its complex pathogenesis involving central sensitisation, autonomic dysfunction, inflammation, and neurological irregularities, and examining how exercise impacts symptom exacerbation caused by external stressors and comorbid conditions., Methods: This review synthesises evidence from current literature focusing on the benefits of structured and personalised exercise programmes in FM management. It discusses the importance of specifying exercise type, intensity, frequency, duration, and progression tailored to individual patient needs and clinical objectives., Results: Regular physical activity effectively mitigates core aetiopathogenetic mechanisms of FM and improves associated conditions such as stress and obesity. It also provides benefits for preventing other chronic diseases, enhancing well-being, and promoting healthy ageing. Structured and personalised exercise programmes that start with a low-demand protocol and gradually increase exercise volume are most beneficial, by improving patient compliance and reducing the risk of adverse effects., Conclusions: Effective management of FM requires a patient-centred approach integrating both pharmacological and non-pharmacological treatments, with exercise playing a pivotal role. Personalised exercise prescriptions that consider FM patients' specific needs and limitations are crucial for optimising treatment outcomes and enhancing quality of life.

Inflamm-aging refers to the chronic low-grade inflammation that occurs with aging and cellular senescence, and it is linked to various diseases. Understanding the markers involved in inflammation and aging, as well as their interaction with environmental factors and bodily control mechanisms, can provide crucial tools for assessing the resilience (i.e. the ability to adapt and improve) of the human body, particularly in the presence of chronic degenerative conditions or vulnerable life stages, that place the individual and the community to which he belongs in a state of potential fragility. HEBE focuses on physical exercise, along with nutritional and lifestyle recommendations, to reduce systemic inflammation and promote healthy aging. HEBE encompasses multiple research lines (LR). In the ongoing LR1 ("proof of concept"), healthy lifestyle recommendations were provided to University of Milan employees, and changes in quality of life and well-being were assessed using a specialized questionnaire. The first 100 eligible subjects, who expressed their willingness to participate, underwent a personalized physical exercise protocol based on clinical and objective assessments. Biomedical samples were collected at baseline (T0) and follow-up (T1) to establish a shared biobank and identify non-invasive biomarkers that monitor the impact of physical exercise on individual characteristics such as cardiovascular and metabolic health. Subsequently (LR2-LR10), the proof of concept findings will be expanded to include various conditions of vulnerability such as obesity, cancer, endocrine disorders, cardiovascular diseases, infertility, functional syndromes, respiratory disorders, neurodegenerative diseases, and autoimmune conditions. The research lines will leverage the expertise of the 94 participating investigators to form a collaborative network that maximizes the potential for investigation and knowledge exchange. This approach fosters a culture of health promotion and disease prevention. ClinicalTrials.gov Identifier: NCT05815732., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bianchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: To assess body composition by means of BOD POD in the large cohort of Italian Olympic athletes of many sport disciplines (studied at the same time), and to provide possible reference values for body composition in elite athletes., Methods: 1556 elite athletes, who took part in the selection procedure for the 2016 Rio Olympic Games for the National Italian Olympic Committee (CONI), were retrospectively studied. Body composition was determined using air plethysmography-based BOD POD., Results: We observed that Fat Mass (FM) and Fat-free Mass (FFM) should be considered as two mutually independent domains in elite athletes. By performing Principal Component Analysis, we defined two independent main domains (respectively, representing FM and FFM), which presented different trends according to gender and static or dynamic exercise load. Lastly, we reported possible reference values for FM index and FFM index, respectively, representing the largest contributors to FM domain and FFM domain, and calculated as FM or FFM (kg)/height (m 2 )., Conclusions: Our findings might provide a basis to optimize the practical approach to body composition in athletes, highlighting the importance of considering indicators of fat mass and lean mass "simultaneously" and not specularly, according to different sport disciplines as well. Moreover, these data might contribute to standardize reference values for body composition in elite athletes, with a view to potentially helping to monitor and guide training regimens, prevent related detrimental practices and plan cardiometabolic prevention and rehabilitation programs., (© 2023. The Author(s).)

Aim: The mechanisms governing the organism's response to exercise are complex and difficult to study. Spectral analysis of heart rate variability (HRV) could represent a convenient methodology for studying humans' autonomic nervous system (ANS). However, difficulties in interpreting the multitude of correlated HRV-derived indices, mainly when computed over different time segments, may represent a barrier to its usage. This preliminary investigation addressed to elite athletes proposes a novel method describing the cardiac autonomic response to exercise based on multilevel exploratory factor analysis (MEFA), which reduces the multitude of HRV-derived indices to fewer uncorrelated ANS indicators capable of accounting for their interrelationships and overcoming the above difficulties. Methods: The study involved 30 Italian Olympic athletes, divided into 15 cyclists (prevalent high-intensity endurance training) and 15 shooters (prevalent technical training with low-intensity endurance component). All athletes underwent a complete test of a dynamic protocol, constituted by a rest-stand test followed by a stepwise bicycle stress test subdivided into a single bout of progressive endurance (from aerobic to anaerobic) exercise and recovery. Then, by spectral analysis, values of 12 ANS proxies were computed at each time segment (9 epochs in all) of the complete test. Results: We obtained two global ANS indicators (amplitude and frequency), expressing the athletes' overall autonomic response to the complete test, and three dynamic ANS indicators (amplitude, signal self-similarity, and oscillatory), describing the principal dynamics over time of the variability of RR interval (RRV). Globally, cyclists have significantly higher amplitude levels (median ± MAD: cyclists 69.9 ± 20.5; shooters 37.2 ± 19.4) and lower frequency levels (median ± MAD: cyclists 37.4 ± 14.8; shooters 78.2 ± 10.2) than shooters, i.e., a parasympathetic predominance compared to shooters. Regarding the RRV dynamics, the signal self-similarity and oscillatory indicators have the strongest sensitivity in detecting the rest-stand change; the amplitude indicator is highly effective in detecting the athletes' autonomic changes in the exercise fraction; the amplitude and oscillatory indicators present significant differences between cyclists and shooters in specific test epochs. Conclusion: This MEFA application permits a more straightforward representation of the complexity characterizing ANS modulation during exercise, simplifying the interpretation of the HRV-derived indices and facilitating the possible real-life use of this non-invasive methodology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Solaro, Pagani, Spataro and Lucini.)

Background: Overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health; and compared with their normal-weight peers, these individuals tend to have a lower level of self-confidence, and consequently lower physical activity adherence. Due to these self-perceived barriers, the aim of our study was to evaluate the efficacy of an online training program on self-reported physical fitness (SRPF) in children with obesity (OB)., Methods: A total of 32 children with OB carried out physical fitness (PF) tests and were asked to complete the International Fitness Enjoyment Scale (IFIS) questionnaire. The physical fitness tests were the Standing Broad Jump (SBJ), the 6-Min Walking Test (6MWT) and the 4 × 10 m sprint test. Children participated in a 3-weekly 60-min training session through Zoom platform. Before the beginning of the training protocol, OB children were compared with normal weight (NW) ones for PF batteries and the IFIS questionnaire. Changes in performances after the training were assessed by paired Student t and Wilcoxon tests., Results: After the online training program children increased their performance in 6MWT (mean difference (MD) = 54.93; p < 0.0001) in SBJ (MD = 10.00; p = 0.0001) and in 4 × 10 m sprint test (MD = -0.78; p < 0.0001). No differences were found in children's physical fitness perception., Discussion: Our study highlighted how a structured online training program can lead to improvements in PF of children with OB. Instead, the lack of differences in SRPF after the training suggests interesting questions to be explored on the aspects linked to self-perception. Therefore, even if our training protocol could not directly improve SRPF in children with obesity, the enhancement of their PF could be a starting point for achieving this result with a longer training period and consequently improve PA participation for children with OB., Competing Interests: Matteo Vandoni and Vittoria Carnevale Pellino are Academic Editors for PeerJ., (© 2023 Puci et al.)

Physical inactivity increases cardiometabolic risk through a variety of mechanisms, among which alterations of immunological, metabolic, and autonomic control systems may play a pivotal role. Physical inactivity is frequently associated with other factors that may further worsen prognosis. The association between physical inactivity and hypoxia is particularly interesting and characterizes several conditions-whether physiological (e.g., residing or trekking at high altitude and space flights) or pathological (e.g., chronic cardiopulmonary diseases and COVID-19). In this randomized intervention study, we investigated the combined effects of physical inactivity and hypoxia on autonomic control in eleven healthy and physically active male volunteers, both at baseline (ambulatory) conditions and, in a randomized order, hypoxic ambulatory, hypoxic bedrest, and normoxic bedrest (i.e., a simple experimental model of physical inactivity). Autoregressive spectral analysis of cardiovascular variabilities was employed to assess cardiac autonomic control. Notably, we found hypoxia to be associated with an impairment of cardiac autonomic control, especially when combined with bedrest. In particular, we observed an impairment of indices of baroreflex control, a reduction in the marker of prevalent vagal control to the SA node, and an increase in the marker of sympathetic control to vasculature.

Exercise is one of the major determinants of a healthy lifestyle, which is particularly important in childhood and serves as a powerful preventive tool. On the other hand, obesity and arterial hypertension rates are increasing in children, representing a huge risk for developing major cardiovascular and metabolic diseases in adult life. Of fundamental importance is the modality and volume of exercise required to obtain benefits. In this feasibility study, we considered a group of obese children, studied before and after a 12-week online exercise training program, and subdivided the participants into two groups considering the volume of exercise performed (above or below 1200 MET·min/week). This threshold level was applied in two different ways: subdivision A considered the total weekly physical activity volume (considering both time spent walking for at least 10 min consecutively and time spent performing structured exercise) and subdivision B considered only the weekly volume of structured exercise. We assessed autonomic and metabolic control and auxological and lifestyle parameters. We observed that the improved volume of structured exercise was associated with reduced arterial pressure percentile only in subdivision B and an improvement in markers of vagal and metabolic control was evident. Moreover, the 12-week online exercise training program, defined considering individual fitness level and progressively adapted as the goal was reached, proved to be sustainable from an economical and organizational point of view.

Physical activity (PA) is a crucial factor in preventing and treating obesity and related complications. In this one-arm pre−post longitudinal prospective study, we evaluated the effects of a 12-week online supervised training program on cardiac morphology, function and blood pressure (BP) in children with obesity. The training program consisted of three sessions per week, each lasting 60 min. Advanced echocardiographic imaging (tissue Doppler and longitudinal strain analysis) was used to detect subclinical changes in heart function. Categorical variables were described as counts and percentages; quantitative variables as the mean and standard deviation (SD) as they were normally distributed (Shapiro−Wilks test). Pre−post comparisons were made with a paired t-test. A total of 27/38 (71%) enrolled patients (18M/9F, 11 ± 2 years) completed the training protocol and were considered in the analysis. At baseline, no hypertensive patient was noted; all echocardiographic variables were within the normal range. After training, we observed a significant reduction in BP parameters, including systolic BP values and Z-score, diastolic BP values, centiles and Z-score, and mean arterial pressure (all p < 0.05). Significant variations in echocardiographic interventricular septum (IVSd) thickness (p = 0.011), IVSd Z-score (p = 0.001), left ventricular (LV) end-diastolic diameter (p = 0.045), LV posterior wall thickness Z-score (p = 0.017), and LV global longitudinal strain (p = 0.016) were detected. No differences in LV diastolic function and right ventricular strain were noted. PA plays a decisive role in improving BP control and has benefits on left ventricle systolic function, representing a strategic approach to limit CV risk. Online exercise could be an excellent method of training in children with obesity.

Workplace health promotion programs and services offered by insurers may play a fundamental role to foster health/well-being and to prevent chronic diseases. To this end, they should be tailored to companies/employees’ requirements and characteristics. In particular, age needs to be taken into account, considering both that young age workers are generally healthy, and that young age is the best period in lifespan to address prevention and instilling healthy behaviors. We employed an anonymous, simple web-based questionnaire (filled out by 1305 employees) which furnishes data regarding lifestyle (nutrition, exercise, smoking, stress, sleep, etc.), some of which were used to build a unique descriptor (Lifestyle Index; 0−100 higher scores being healthier). We considered three subgroups accordingly to age: ≤30; between 30 and 50; >50 years. This study showed age influences lifestyle and stress perception in the working population: the youngest employees (both men and women) presented the worst lifestyle index, particularly in its stress component. This observation may potentially be useful to tailor workplace health promotion programs and to personalize insurance protocols and services offered to employees. The practical message of our study is that in healthy young people focusing only on medical parameters (frequently within normal ranges in this cohort), albeit important, may be not sufficient to foster proactive actions to prevent chronic non-communicable diseases in adult life. Vice versa, driving their attention on current behaviors might elicit their proactive role to improve lifestyle, getting immediate advantages such as well-being improvement and the possibility to best manage stress.

Chronic stress may represent one of the most important factors that negatively affects the health and performance of athletes. Finding a way to introduce psychological strategies to manage stress in everyday training routines is challenging, particularly in junior teams. We also must consider that a stress management intervention should be regarded as "efficacious" only if its application results in improvement of the complex underlying pathogenetic substratum, which considers mechanistically interrelated factors, such as immunological, endocrine and autonomic controls further to psychological functioning and behavior. In this study, we investigated the feasibility of implementing, in a standard training routine of the junior team of the Italian major soccer league, a stress management program based on mental relaxation training (MRT). We evaluated its effects on stress perception and cardiac autonomic regulation as assessed by means of ANSI, a single composite percentile-ranked proxy of autonomic balance, which is free of gender and age bias, economical, and simple to apply in a clinical setting. We observed that the simple employed MRT intervention was feasible in a female junior soccer team and was associated with a reduced perception of stress, an improved perception of overall health, and a betterment of cardiac autonomic control. This data may corroborate the scientific literature that indicates psychological intervention based on MRT as an efficacious strategy to improve performance, managing negative stress effects on cardiac autonomic control.

Purpose: The goal of this study on Spinal Cord Injury (SCI) patients with cervical or thoracic lesion was to assess whether disturbances of ANS control, according to location, might differently affect vagal and sympatho-vagal markers during sleep and orthostatic challenge. We analyzed with linear and nonlinear techniques beat-by-beat RR and arterial pressure (and respiration) variability signals, extracted from a polysomnographic study and a rest-tilt test. We considered spontaneous or induced sympathetic excitation, as obtained shifting from non-REM to REM sleep or from rest to passive tilt. We obtained evidence of ANS cardiac (dys)regulation, of greater importance for gradually proximal location (i.e., cervical) SCI, compatible with a progressive loss of modulatory role of sympathetic afferents to the spinal cord. Furthermore, in accordance with the dual, vagal and sympathetic bidirectional innervation, the results suggest that vagally mediated negative feedback baroreflexes were substantially maintained in all cases. Conversely, the LF and HF balance (expressed specifically by normalized units) appeared to be negatively affected by SCI, particularly in the case of cervical lesion (group p = 0.006, interaction p = 0.011). Multivariate analysis of cardiovascular variability may be a convenient technique to assess autonomic responsiveness and alteration of functionality in patients with SCI addressing selectively vagal or sympathetic alterations and injury location. This contention requires confirmatory studies with a larger population.

Athletic performance is determined by many factors, such as cardiorespiratory fitness, muscular strength and psychological features, which all interact simultaneously. The large Italian National Olympic Committee database of Olympic athletes offers a unique healthy population to verify the strength of the interplay among a number of major elements of training, including autonomic nervous system (ANS) modulation, biochemical indicators and body composition, in a system medicine approach. This observational, retrospective study involved 583 individuals. As part of the yearly precompetitive examination, cardiac autonomic (heart rate variability), psychological, physical (cycloergometer stress test), biochemical and body composition (BOD POD) evaluations were performed. In subsequent analysis, we first considered the relationship between body composition and single individual variables in a simple correlation matrix, including a multitude of variables; then, Exploratory Factor Analysis (EFA) restricted the information to six latent domains, each combining congruent information in relation to body composition. Finally, we employed a multiple quantile regression model to evaluate possible relationships between ANSIs (index capable of synthetizing ANS regulation) and the latent domains indicated by EFA reflecting body composition. We observed a clear relationship between ANS and body mass composition parameters, as indicated by both bivariate correlations and the quantile regression result of ANSIs versus the latent domain aggregating mainly body composition data expressed in % ( p = 0.002). In conclusion, these results suggest that specific training may elicit parallel adaptation of ANS control and body composition. The analysis of Olympic athletes' data allowed us to obtain a better understanding of the complex, multidimensional factors involved in determining sport performance. The latter appears to be determined by the simultaneous interaction not only of cardiorespiratory fitness, muscular strength and psychological features, but also of ANS cardiovascular modulation and body composition.

Obesity is associated with an increased risk of several chronic comorbidities, which may also be determined by dysfunctional autonomic nervous system (ANS). The influence of bariatric surgery (BS) on ANS balance was explored in previous studies, but with high heterogeneity in both the assessment timing and methods employed. In the present observational study, we applied a clinical protocol which considers two subsequent phases. Twenty-nine non-diabetic obese subjects were studied at baseline (T0), after one month of lifestyle modification (prehabilitation) (phase 1-T1), and after eight months following BS (phase 2-T2). ANS regulation was assessed across the three study epochs by means of ANSI, a single composite percent-ranked proxy of autonomic balance, being free of gender and age bias, economical and simple to apply in a clinical setting. The aim of the present study was to investigate the effects of the clinical protocol based on prehabilitation and subsequent BS on the ANS regulation by means of ANSI. Potential intertwined correlations with metabolic parameters were also investigated. Notably, we observed a progressive improvement in ANS control, even by employing ANSI. Moreover, the reduction in the markers of sympathetic overactivity was found to significantly correlate with the amelioration in some metabolic parameters (fasting glucose, insulin levels, and waist circumference), as well as in stress and tiredness perception. In conclusion, this study provides convincing evidence that a unitary proxy of cardiac autonomic regulation (CAR) may reflect the progressive improvement in autonomic regulation following behavioral and surgical interventions in obese patients. Intriguingly, this might contribute to reducing cardiovascular and metabolic risk.

COVID-19 restrictions have dramatically reduced the active lifestyle and physical activity (PA) levels in the whole population, a situation that can contribute to weight gain and to develop obesity. To improve physical fitness (PF) in children with obesity during COVID-19 restrictions, sport specialists started to deliver physical training through tele-exercise. For these reasons, the aim of this study was to evaluate the effects of a 12-week online supervised training program in children with obesity on different PF components and PA levels. We enrolled a total of 40 Caucasian children (9 F/31 M; aged 11 ± 1.9 years) with obesity. The data collection consisted of a series of anthropometric measures, the PAQ-C questionnaire, and PF tests, valid and reliable tools to assess PF in children. We used a Wilcoxon's t -test and a Student's t -test, as appropriate, to assess the differences before and after the training protocol. A total of 37 patients completed the training protocol and were considered in the analysis. Our results show an improvement in all the PF tests, a reduction in the BMI z-score, the waist circumference, and in the waist-to-height ratio, and an increased PA level. In conclusion, the results of our study show that an online supervised training program is effective to promote PA, improving PF and reducing the BMI z-score in children with obesity.

The association between left atrial (LA) impairment and cardiovascular diseases (CVD) and between dyslipidaemia and CVD are well known. The present study aims to investigate the relationships between metabolic factors and LA dimensions and compliance, as well as test the hypothesis that metabolic factors influence LA function independent from hemodynamic mechanisms. Arterial blood pressure (BP), waist and hip circumference, metabolic indices, and a complete echocardiographic assessment were obtained from 148 selected inhabitants (M/F 89/59; age 20−86 years) of Linosa Island, who had no history of CVD. At enrollment, 27.7% of the subjects met the criteria for metabolic syndrome (MetS) and 15.5% for arterial hypertension (HTN). LA compliance was reduced in subjects with MetS compared to those without (53 ± 27% vs. 71 ± 29%, p = 0.04) and was even lower (32 ± 17%, p = 0.01) in those with MetS and HTN. At multiple regression analysis, the presence of MetS independently determined LA maximal area (r = 0.56, p < 0.001), whereas systolic BP and the total cholesterol/HDL cholesterol ratio determined LA compliance (r = 0.41, p < 0.001). In an apparently healthy population with a high prevalence of MetS, dyslipidaemia seems to independently influence LA compliance. At a 5-year follow-up, LA compliance was reduced in both all-cause and CVD mortality groups, and markedly impaired in those who died of CVD. These findings may contribute to understanding the prognostic role of LA function in CVD and strengthen the need for early and accurate lipid control strategies.

QT interval (QT) variability analysis provides pathophysiological and prognostic information utilized in cardiac and non-cardiac diseases, complementary to those obtained from the analysis of heart period (HP) variability. An increased QT variability has been associated to a higher risk for cardiac events and poorest prognosis. Autonomic cardiovascular adaptation to internal and external challenges, such those occurring in athletes exposed to high levels of physical stress and in ageing could also be deepen by analyzing QT variability, searching for early prognostic signatures. The aim of the study was to analyze the QT variability and cardiac control complexity in a group of middle-aged half-marathon runners at baseline (B) and at a 10-year follow-up (FU). We found that the overall QT variability decreased at FU, despite the inescapable increase in age (52.3 ± 8.0 years at FU). This change was accompanied by an increase of the HP variability complexity without changes of the QT variability complexity. Of notice, over the years, the group of athletes maintained their regular physical activity by switching to a moderate intensity rather than strenuous. In conclusion, regular and moderate exercise over the years was beneficial for this group of athletes, as reflected by the decreased overall QT variability that is known to be associated to lower cardiovascular risk. The concomitant enhanced cardiac control complexity also suggests a trend opposite to what usually occurs with ageing, resulting in a more flexible cardiac control, typical of younger people., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 De Maria, Lucini, Gois, Catai, Perego, Malacarne, Pagani, Porta and Dalla Vecchia.)

The increased cardiometabolic risk observed in breast cancer survivors (BCS) is due to multiple mechanisms: Hormonal and immunological dysfunction are well-identified ones, while cardiac autonomic regulation (CAR) is less recognized but may play a new complementary role particularly relevant when considering conditions and behaviors associated with a better prognosis in BCS, such as physical training. This observational study investigated a group of consecutive (172) BCS subdivided in two groups: those who reached the physical activity goals above 600 (MET·min/week) and those who did not. We assessed CAR by autoregressive spectral analysis of cardiovascular variabilities (considering in particular the unitary autonomic nervous system index-ANSI), body mass composition, stress perception and lifestyle in order to verify possible differences due to execution of physical activity. Subjects who spontaneously met physical activity recommendations presented a better autonomic, metabolic and psychological profile compared to those who did not. Lower physical activity volume, poor metabolic parameters, increased stress and fatigue perception may cluster together, leading to worsened CAR. This control mechanism may play a complementary role in determining the increased cardiometabolic risk observed in BCS. Furthermore, it may also explain, albeit in part, the better prognosis observed in patients following interventions aiming to improve the sympathetic-parasympathetic balance, such as physical training, using a personalized medicine approach.

In the last decade, endocrine therapy strategies in perimenopausal women with hormone-responsive early breast cancer (BC) have changed and now ovarian function suppression (OFS) is recommended for the majority of patients. Side effects of OFS mimic menopausal symptoms, including hot flushes, sweats, weight gain, and sexual dysfunction, which may negatively impact quality of life (QoL). Aims of the Take Care Project are the education of physicians and patients to have all the information (medical and nonmedical) they need to manage menopausal symptoms by distributing educational materials useful to face menopause. Four different areas have been identified by surveys conducted among physicians and young patients: for each area, interventions and tools have been elaborated by a doctor and nonphysician professionals of these identified areas, to offer the widest information available. Clinical and practical suggestions have been provided. Based on the evidence given, we strongly suggest setting up a multidisciplinary team for the treatment planning of young patients with BC, which could help patients to face and manage their new menopause condition. The reduction of side effects and the improvement in QoL should be the best ally to treat young patients with BC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Workplace Health Promotion (WHP) may improve health, productivity and safety and reduce absenteeism. However, although desirable, it is difficult to design tailored (and thus effective) WHP programs, particularly in small-medium companies, which rarely have access to sufficient economic and organizational resources. In this study, 1305 employees filled out an online anonymous lifestyle questionnaire hosted on the website of a non-profit organization, which aims to promote a healthy lifestyle among workers. The data show gender differences regarding stress perception and, in the working population meeting current physical activity recommendations (threshold = 600 MET·min/week), they point out the evidence of a better psychological and nutrition profile, a perception of better job performance, and improved sleep and health quality. Moreover, a unitary index (ranging from 0-100 (with higher scores being healthier)), combining self-reported metrics for diet, exercise and stress, was significantly higher in active employees (67.51 ± 12.46 vs. 39.84 ± 18.34, p < 0.001). The possibility of assessing individual lifestyle in an easy, timely and cost-effective manner, offers the opportunity to collect grouped data useful to drive tailored WHP policies and to have metric to quantify results of interventions. This potentiality may help in creating effective programs and in improving employees' and companies' motivation and attitude towards a feasible WHP.

Aim: In this study we sought to assess whether in elite athletes the physiological increase in cardiac mass attending severe long-term training leading to athlete's heart is accompanied by an improvement of autonomic performance, as assessed by post exercise vagal indices and a novel unitary Autonomic Nervous System Index for sports (ANSIs)., Methods: The study involved 500 elite athletes (23.9 ± 6.4 years) participating in a screening organised by the National Italian Olympic Committee. All subjects underwent a complete medical examination, rest and stand autonomic assessment (heart rate variability) as well as bicycle exercise. ANSIs was also derived as radar plot from rest, stand and heart rate recovery individual proxies of autonomic nervous system regulation. All subjects were grouped into those with left ventricular hypertrophy present (LVH(+)), or not (LVH(-)), according to recognised thresholds., Results: We observed that LVH(+) athletes (24.8%) showed a marked increase of post-exercise vagal indices (p < 0.001) and of ANSIs (p < 0.001), while no difference was observed for heart-rate variability indices. These changes were contingent upon sport intensity categories., Conclusions: Elite athletes with physiological cardiac hypertrophy (LVH(+)) present a selective profile of indices of autonomic nervous system performance, characterised by increases of markers of vagal recovery and of the novel unitary autonomic index for sports while RR variance and spectral indices seem to be unmodified. Athlete's heart may be characterised by a specific combination of anatomical and neurocardiac remodeling. This approach might furnish potential warning signs differentiating normal training induced physiology from pathological adaptation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Early obesity predicts initial modifications in cardiac and vascular autonomic regulation. The aim of this study was to assess the possible interaction between non-invasive measures of autonomic cardiovascular control and peripheral endothelium regulation in children with overweight and obesity. We involved 114 young subjects (77M/37F, 12.7 ± 2.2 years) with normal weight (NW, n = 46) to overweight or obesity (OB, n = 68). Multivariate statistical techniques utilizing a collection of modern indices of autonomic regulation, adiposity indexes and metabolic profile were employed. Resting values show substantial equivalence of data. Conversely, blood pressure variance is greater in NW/OB groups. The correlation matrix between major autonomic and metabolic/hemodynamic variables shows a clustered significant correlation between homogeneous indices. A significant correlation between metabolic indices and endothelial and autonomic control, mostly in its vascular end, was recorded. Particularly, the alpha index is significantly correlated with triglycerides (r = -0.261) and endothelial indices (RHI, r = 0.276). Children with obesity show a link between indices of autonomic and endothelial function, fat distribution and metabolic profile. The optimization of autonomic control, for instance by exercise/nutrition interventions, could potentially prevent/delay the occurrence of structural vascular damage leading to reduced cardiovascular health.

Introduction: Sleep-related breathing disorders are highly prevalent in patients with ischemic stroke. Among sleep-disordered breathing disorders, obstructive sleep apnea is the most represented one, but central sleep apnea, isolated or in the context of a periodic breathing/Cheyne-Stokes respiration, is frequently reported in these patients. Altered baroreflex responses have been reported in the acute phases of a cerebral event., Methods: We conducted, in a group of patients with ischemic stroke (n=60), a prospective 3-month follow-up physiological study to describe the breathing pattern during sleep and baroreflex sensitivity in the acute phase and in the recovery phase., Results: In the acute phase, within 10 days from the onset of symptoms, 22.4% of patients had a normal breathing pattern, 40.3% had an obstructive pattern, 16.4% had a central pattern, and 29.9% showed a mixed pattern. Smaller variations in the Apnea-Hypopnea Index were found in normal breathing and obstructive groups (ΔAHI 2.1±4.1 and -2.8±11.6, respectively) in comparison with central and mixed patterns (ΔAHI -6.9±15.1 and -12.5±13.1, respectively; ANOVA p =0.01). The obstructive pattern became the most frequent pattern, in 38.3% of patients at baseline and 61.7% of patients at follow-up. Modification of baroreflex sensitivity over time was influenced by the site of the lesion and by the sleep disorder pattern in the acute phase (MANOVA p =0.005)., Conclusion: We suggest that a down-regulation of autonomic activity, possibly related to reduced vagal modulation, may help the recovery after stroke, or a transitory disconnection from the cortical node that participates in the regulation of sympathetic outflow., Competing Interests: Dr Alessia Riglietti reports grants from ABREOC (Scientific Research Advisory Board of the Ente Ospedaliero Cantonale), Doctor PierLuigi Crivelli Foundation and Cecilia Augusta Foundation, during the conduct of the study. Dr Carlo W Cereda is a member of the iSchemaView Medical and Scientific Advisory Board, but this institution played no role in current research . Prof. Dr Marco Pons report grants from ABREOC, Dr Pieruigi Crivelli Foundation and Cecilia Augusta Foundation, during the conduct of the study. The authors have no other financial support or conflicts of interest to declare., (© 2021 Riglietti et al.)

Background: The prevalence of pediatric metabolic syndrome is usually closely linked to overweight and obesity; however, this condition has also been described in children with disabilities. We performed a multivariate pattern analysis of metabolic profiles in neurologically impaired children and adolescents in order to reveal patterns and crucial biomarkers among highly interrelated variables., Patients and Methods: We retrospectively reviewed 44 cases of patients (25M/19F, mean age 12.9 ± 8.0) with severe disabilities. Clinical and anthropometric parameters, body composition, blood pressure, and metabolic and endocrinological assessment (fasting blood glucose, insulin, total cholesterol, high-density lipoprotein cholesterol, triglycerides, glutamic oxaloacetic transaminase, glutamate pyruvate transaminase, gamma-glutamyl transpeptidase) were recorded in all patients. As a control group, we evaluated 120 healthy children and adolescents (61M/59F, mean age 12.9 ± 2.7)., Results: In the univariate analysis, the children-with-disabilities group showed a more dispersed distribution, thus with higher variability of the features related to glucose metabolism and insulin resistance (IR) compared to the healthy controls. The principal component (PC1), which emerged from the PC analysis conducted on the merged dataset and characterized by these variables, was crucial in describing the differences between the children-with-disabilities group and controls., Conclusion: Children and adolescents with disabilities displayed a different metabolic profile compared to controls. Metabolic syndrome (MetS), particularly glucose metabolism and IR, is a crucial point to consider in the treatment and care of this fragile pediatric population. Early detection of the interrelated variables and intervention on these modifiable risk factors for metabolic disturbances play a central role in pediatric health and life expectancy in patients with a severe disability.

Objective: In the last years, a debate exists about type, intensity and frequency of physical exercise that is really indicated to protect healthy subjects from cardiovascular disease. Regular physical training has been associated with an improved cardiovascular risk profile, but it has also been demonstrated that strenuous and uncontrolled physical exercise could be dangerous, in terms of increased cardiovascular morbidity and mortality. In the present study, we evaluated a group of 35 amateur half-marathon runners, who were likewise studied 10 years before (B). The results of B suggested that an increased cardiac sympathetic modulation could potentially represent a negative prognostic factor. The aim of this follow-up was to assess the medium-long-term effects of moderate to vigorous physical training on the cardiovascular neural control, cardiac function and occurrence of cardiovascular diseases., Methods: Each enrolled subject underwent: (1) an interview and physical examination to ascertain the presence of cardiovascular disease; (2) standing test to evaluate the cardiovascular neural control by means of heart rate variability (HRV), arterial blood pressure (AP) variability and baroreflex sensitivity (BRS); (3) transthoracic echocardiography to evaluate cardiac function., Results: At 10-year follow-up (FU), in this group of middle-aged athletes the occurrence of cardiovascular diseases was low, not unlike that of the overall population. The results of HRV analysis showed a decreased sympathetic and increased vagal modulation directed to the heart, compared with B. In addition, HRV, AP variability and BRS indices showed a physiological response to active standing. Finally, athletes had normal echocardiographic measures., Conclusion: We conclude that in our group of athletes a regular moderate-vigorous physical training through the 10 years was quite beneficial as the prevalence of sympathetic cardiac modulation observed at B was not accompanied by increased cardiovascular risk, on the contrary a slight prevalence of vagal indices was observed at FU., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In the context of functional determinants of cardiovascular risk, a simple excess in body weight, as indexed by a rise in body mass index (BMI), plays a significant, well-recognized causal role. Conversely, BMI reductions toward normal result in an improvement of risk. Obesity is associated with impaired cardiac autonomic regulation (CAR), through either vagal or sympathetic mechanisms, which could favor the tendency to foster hypertension. Here we study the changing properties of the relationship between increasing grades of BMI and CAR in a population of 756 healthy subjects (age 35.9 ± 12.41 years, 37.4% males, 21.6% overweight, and 16% obese). Evaluation of CAR is based on autoregressive spectral analysis of short-term RR interval and systolic arterial pressure variability, from which a multitude of indices, treated overall as autonomic nervous system (ANS) proxies, is derived. Inspection of the study hypothesis that elevated BMI conditions associate significantly with alterations of CAR, independently of age and gender, is carried out using a mix of statistical transformations, exploratory factor analysis, non-parametric testing procedures, and graphical tools particularly well suited to address alterations of CAR as a disturbed process. In particular, to remove the effects of the inter-individual variability, deriving from components like age, gender or ethnicity, and to reduce the number of ANS proxies, we set up six age-and-gender-adjusted CAR indicators, corresponding to four ANS latent domains (oscillatory, amplitude, pressure, and pulse), cardiac baroreflex regulation, and autonomic nervous system index (ANSI). An impairment of the CAR indicators is overall evident in the overweight group and more marked in the obesity group. Empirical evidence is strong (9/9 concordant non-parametric test results) for pressure domain, almost strong (8/9) for ANSI, medium-strong for baroreflex (6/9) and pulse (7/9), weak for oscillatory (2/9) and amplitude (1/9) domains. In addition, the distribution of the CAR indicators corresponding to pressure, pulse, baroreflex, and ANSI is skewed toward the unfavorable abscissa extremity, particularly in the obese group. The significant association of increased BMI with progressive impairments of CAR regarding specifically the pressure domain and the overall ANS performance might underscore the strong hypertensive tendency observed in obesity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Solaro, Pagani and Lucini.)

The current literature contains multiple examples of exercise interventions to foster health and to prevent/treat many chronic non-communicable diseases; stress and functional syndromes. On the other hand, sedentariness is increasing and to transform a sedentary subject into a regular exerciser is not only very difficult but considered by some unrealistic in current clinical practice. Ideally a physical activity intervention may be considered actually efficacious when it outgrows the research setting and becomes embedded in a system, ensuring maintenance and sustainability of its health benefits. Physicians need specific skills to improve patients' exercise habits. These range from traditional clinical competencies, to technical competencies to correctly prescribe exercise, to competencies in behavioral medicine to motivate the subject. From a behavioral and medical point of view, an exercise prescription may be considered correct only if the subject actually performs the prescribed exercise and this results in an improvement of physiological mechanisms such as endocrine, immunological and autonomic controls. Here we describe a model of intervention intended to nurture exercise prescription in everyday clinical setting. It aims to a tailored prescription, starts from the subject's assessment, continues defining clinical goals/possible limitations and ends when the subject is performing exercise obtaining results.

The COVID-19 lockdown imposed radical changes in the lifestyles of the population through isolation measures, with considerable health, social, psychological and economic consequences. Lockdown measures may have exacerbated negative population behaviors regarding exercise and nutrition, with risk of weight gain and obesity, collectively predisposing to increased cardiometabolic risk and mortality. At particular risk of deleterious consequences were patients such as those affected by chronic non communicable diseases (CNCD). The benefits of regular exercise are evident at several levels of CNCD prevention, however, from a public health standpoint, it is important to consider they are also related to improved stress management, work/academic performance, and reduced illegal behavior, isolation and depression. Therefore, during enforced isolation, a primary goal for all individuals is to maintain energy balance. During lockdown, several lifestyle interventions were posted online, with the internet playing a major role in exercise and fitness promotion. Among these one must recognize the ambitious "#StayHomeStayFit" project by the University of Milan, providing useful general information and trustworthy advice regarding nutrition, physical activity, and psychological support, for the general population in a time of need. Data showed a total of 21224 views on various social media and webpages during the reference period, with a mean time of 4' 17'' spent per page/video. Given the health risks associated with population physical inactivity and unhealthy lifestyle, policymakers should evaluate the benefits of projects such as #StayHomeStayFit and consider how to maximize population perception and reach. After all, additional COVID-19 lockdowns might be implemented in the future.

It is well recognized that regular physical activity may improve cardiac autonomic regulation preventing chronic non-communicable diseases. Accordingly, the assessment of cardiac autonomic regulation (CAR) with non-invasive techniques, such as RR interval Variability (V) might be of practical interest. We studied 56 soccer players (21.2 ± 4.2 years.) and 56 controls (22.2 ± 1.5 years.) and used a ranked Autonomic Nervous System Index (ANSI), resulting from the combination of multivariate statistical methodologies applied to spectral analysis derived indices from RRV. We hypothesized that ANSI would be higher in soccer players as compared to controls ( p < 0.001) and that values would be greatest in defenders and midfielders, who are known to run longer distances during competitions. Conversely in the intrinsically stationary goalkeepers ANSI would be similar to controls. Our data show that it is possible to assess the overall level of autonomic performance in soccer players as compared to the general population, using a ranked composite autonomic proxy (ANSI). This approach suggests as well that CAR is better in those players who during competitions run for a greater distance. We conclude that it is possible to highlight the differences in autonomic profile due to distinct exercise routines, using ANSI, a simple ranked, composite autonomic proxy.

In athletes, spectral analysis of HR variability (HRV) has been shown capable to detect the adaptational changes in sympatho-vagal control attending physical training. So far, studies investigated autonomic nervous system (ANS) changes occurring with endurance training, whereas adaptations to markedly different exercise modes, for example, strength training, have never been investigated. We assessed the changes in cardiac ANS parameters during long-term training in weight lifters of the Italian team preparing for the European Championship, where athletes competed for obtaining the pass for Olympic Games. We investigated nine athletes. Subject trained 3 sessions/day, 6 days a week. The intensity of strength exercises varied from 70% to 95% 1 RM. Training load (TL) was calculated as: volume (min) × intensity (%1RM).All ANS parameters were significantly and highly correlated on an individual basis to the dose of exercise with a second-order regression model (r 2 ranged from 0.96 to 0.99; P < 0.001). The low-frequency (LF) component of HRV and LF/HF ratio showed an initial increase with the progression of TL and then a decrease, resembling a bell-shaped curve with a minimum at the highest TL. The high-frequency (HF) component of HRV and R-R interval showed a reciprocal pattern, with an initial decrease with progression of TL followed by an increase, resembling an U-shaped curve with a maximum at the highest TL. These adaptations were at the opposite to those previously reported in endurance athletes. These results suggest that in Olympic weight lifters, ANS adaptations to training are dose-related on individual basis and that ANS adaptations are mainly sport-specific., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Cardiovascular regulation and autonomic function change across sleep stages and compared to wake. Little information is present in literature about cardiac control during sleep especially in relation to new information-theoretic quantities such as synergy and redundancy. In the present work we compute synergy and redundancy of baroreflex and non-baroreflex components of the cardiac control according to two information-theoretic approaches, namely predictive information decomposition (PID) and minimal mutual information (MMI) methods. We applied a bivariate approach to heart period (HP) and systolic arterial pressure (SAP) beat-to-beat variability series during sleep in a healthy subject. PID approach computes the net balance between synergy and redundancy, while MMI calculates the two quantities as separate entities. Results suggested that: i) redundancy was dominant over synergy during NREM phases; ii) redundancy increased during NREM phase; iii) synergy did not change across the sleep stages. We interpret this result as a consequence of the vagal enhancement, slowing and deepening of respiration during NREM phases. These preliminary findings support the potential of assessing redundancy/synergy of baroreflex-related and unrelated regulations during sleep to improve our knowledge about physiological mechanisms.

Interests about the fine underpinnings of cardiovascular beat-by-beat variability have historical roots. Over the last decades, various aspects of the relationships between arterial pressure and heart period were taken as a proxy of the baroreflex in physiology and medicine, stimulating the interest of investigators in several interconnected scientific fields, in particular, bioengineering, neurophysiology, and clinical medicine. Studies of the overall system facilitated the emergence of a simplified negative (vagal) feedback model of the baroreflex and overshadowed the simultaneous interaction with excitatory, sympathetic positive-feedback mechanisms that would, however, better suit the model of a "paired antagonistic (parasympathetic/sympathetic) innervation of the internal organs." From the bioengineering side, the simplicity of obtaining the series of subsequent RR intervals stimulated the analysis of beat-by-beat variations, providing a multitude of heart rate variability (HRV) indices considered as proxies of the underlying sympatho-vagal balance, and participating to the management of several important clinical conditions, such as hypertension. In this context, advanced statistical methods, used in an integrated manner and controlling for age and gender biases, might help shed new light on the relationship between cardiac baroreflex, assessed by the frequency domain index α, and the HRV indices with the varying of systolic arterial pressure (SAP) levels. The focus is also on a novel unitary Autonomic Nervous System Index (ANSI) built as a synthesis of HRV considering its three most informative proxies [RR, RR variance, and the rest-stand difference in the normalized power of low-frequency (LF) variability component]. Data from a relatively large set of healthy subjects ( n = 1154) with a broad range of SAP [from normal ( n Nt = 778) to elevated ( n Ht = 232)] show that, e.g., α and ANSI significantly correlate overall ( r = 0.523, p < 0.001), and that this correlation is lower in hypertensives ( r = 0.444, p < 0.001) and higher in pre-hypertensives ( r = 0.618, p < 0.001) than in normotensives ( r = 0.5, p < 0.001). That suggests the existence of curvilinear "umbrella" patterns that might better describe the effects of the SAP states on the relationships between baroreflex and HRV. By a mix of robust, non-parametric and resampling statistical techniques, we give empirical support to this study hypothesis and show that the pre-hypertensive group results at the apex/bottom in most of the studied trends.

Objective: Traditional definition of sample entropy (SampEn), here referred to as global SampEn (GSampEn), provides a conditional entropy estimate that blurs the local statistical properties of the time series. We hypothesized that a local version of SampEn (LSampEn) might be more powerful in the presence of determinism than GSampEn., Methods: LSampEn was computed by calculating the probability of the current sample conditioned on each reference pattern and averaging it over all reference patterns. The improved ability of LSampEn compared to GSampEn was demonstrated by simulating deterministic periodic, deterministic chaotic, and linear stochastic dynamics corrupted by additive noise and over real cardiovascular variability series recorded from 16 healthy subjects (max-min age range: 22-58 years) during incremental bicycle ergometer exercise., Results: We found that: i) LSampEn is more robust in describing deterministic periodic or nonlinear features in the presence of additive noise than GSampEn, ii) in association with a surrogate approach, LSampEn is more powerful in detecting nonlinear dynamics than GSampEn, iii) LSampEn and GSampEn are equivalent in the presence of stochastic linear dynamics, and iv) only LSampEn can detect the decrease of complexity of heart period variability during bicycle exercise being a likely hallmark of sympathetic activation., Conclusion: LSampEn preserves the GSampEn capability in characterizing the complexity of short sequences but improves its reliability in the presence of deterministic patterns featuring sharp state transitions and nonlinear dynamics., Significance: Variations of complexity can be measured with a greater statistical power over short series using LSampEn, especially when nonlinear features are present.

The arm of the baroreflex (BR) controlling peripheral resistances (PR), labeled as BR of PR (prBR), was characterized through an extension of the cardiac BR (cBR) sequence analysis. The method exploits recordings of skin blood flow (SBF) from the palm of the non-dominant hand via a laser Doppler flowmeter and of arterial pressure (AP) from the middle finger of the same hand via a plethysmographic device. PR was estimated beat-by-beat as the ratio of mean AP to mean SBF computed over the same heart period (HP). Peripheral resistances-diastolic arterial pressure (PR-DAP) sequences featuring simultaneous increases of PR and decreases of diastolic AP (DAP) or vice versa were identified and the slope of the regression line in the (DAP, PR) plane was taken as an estimate of prBR sensitivity (BRS prBR ). The percentage of prBR sequences (SEQ% prBR ) was taken as a measure of prBR involvement and the prBR effectiveness index (EI prBR ) was computed as the fraction of DAP sequences capable to drive antiparallel PR variations. Analogous markers were computed over cBR from HP and systolic AP (SAP) variability [i.e., cBR sensitivity (BRS cBR ), percentage of cBR sequences (SEQ% cBR ) , and effectiveness index of the cBR (EI cBR )]. prBR and cBR were typified during incremental light-to-moderate bicycle ergometer exercise at 10, 20, and 30% of the maximum effort in 16 healthy subjects (aged from 22 to 58 years, six males). We found that: (i) BRS cBR decreased gradually with the challenge, while BRS prBR declined only at the heaviest workload; (ii) SEQ% cBR decreased solely at the lightest workload, while the decline of SEQ% prBR was significant regardless of the intensity of the challenge; (iii) EI prBR and EI cBR were not affected by exercise; (iv) after pooling together all the data regardless of the experimental conditions, BRS prBR and BRS cBR were uncorrelated, while SEQ% cBR and SEQ% prBR as well as EI cBR and EI prBR , were significantly and positively correlated; (v) when the correlation between SEQ% cBR and SEQ% prBR and between EI cBR and EI prBR was assessed separately in each experimental condition, it was not systematically detected. This study suggests that prBR characterization provides information complementary to cBR that might be fruitfully exploited to improve patients' risk stratification.

Purpose: Optimal autonomic regulation and stress resilience might be considered critical elements of athletic performance. We hypothesize that a novel unitary autonomic index for sports (ANSIs), together with a somatic stress related symptom score (4SQ) might help characterize athletes who were eventually selected for the Rio 2016 Olympic Games Italian team (Rio +)., Methods: In this retrospective study we examined 778 athletes (age 24.4 ± 6.7 yrs) who underwent a planned yearly pre-participation screening. All athletes underwent clinical, autonomic and exercise ECG evaluation. The combination of vagal and sympathetic indices from RR variability into ANSIs was performed by radar plot and percent ranking of index variables. We assessed (Rio +) versus (Rio -) athletes also after subdivision into three sport intensity groups (low, mid and high intensity)., Results: Overall there were no significant differences between (Rio +) and (Rio -) athletes when considering individual spectral derived variables. Conversely, the unitary Index ANSIs was significantly higher in (Rio +) compared to (Rio -) athletes (respectively 54.5 ± 29.5 and 47.9 ± 28.4 p = 0.014). This difference was particularly evident (p = 0.017) in the group of athletes characterized by both high static and dynamic components. 4SQ was smaller in the (Rio +) group, particularly in the groups of athletes characterized by both low-medium static and dynamic components., Conclusions: ANSIs, a proxy of integrated cardiac autonomic regulation and simple assessment of resilience to stress, may differentiate Italian athletes who were eventually selected for participation in the 2016 Rio Olympic Games from those who were not, suggesting the possibility of a "winning functional phenotype".

In spite of the large body of evidence suggesting Heart Rate Variability (HRV) alone or combined with blood pressure variability (providing an estimate of baroreflex gain) as a useful technique to assess the autonomic regulation of the cardiovascular system, there is still an ongoing debate about methodology, interpretation, and clinical applications. In the present investigation, we hypothesize that non-parametric and multivariate exploratory statistical manipulation of HRV data could provide a novel informational tool useful to differentiate normal controls from clinical groups, such as athletes, or subjects affected by obesity, hypertension, or stress. With a data-driven protocol in 1,352 ambulant subjects, we compute HRV and baroreflex indices from short-term data series as proxies of autonomic (ANS) regulation. We apply a three-step statistical procedure, by first removing age and gender effects. Subsequently, by factor analysis, we extract four ANS latent domains that detain the large majority of information (86.94%), subdivided in oscillatory (40.84%), amplitude (18.04%), pressure (16.48%), and pulse domains (11.58%). Finally, we test the overall capacity to differentiate clinical groups vs. control. To give more practical value and improve readability, statistical results concerning individual discriminant ANS proxies and ANS differentiation profiles are displayed through peculiar graphical tools, i.e., significance diagram and ANS differentiation map, respectively. This approach, which simultaneously uses all available information about the system, shows what domains make up the difference in ANS discrimination. e.g., athletes differ from controls in all domains, but with a graded strength: maximal in the (normalized) oscillatory and in the pulse domains, slightly less in the pressure domain and minimal in the amplitude domain. The application of multiple (non-parametric and exploratory) statistical and graphical tools to ANS proxies defines differentiation profiles that could provide a better understanding of autonomic differences between clinical groups and controls. ANS differentiation map permits to rapidly and simply synthesize the possible difference between clinical groups and controls, evidencing the ANS latent domains that have at least a medium strength of discrimination, while the significance diagram permits to identify the single ANS proxies inside each ANS latent domain that resulted in significant comparisons according to statistical tests.

Since the seminal studies by Sayers (Ergonomics 16:17-32, 1973) and Akselrod et al. (Science 213:220-222, 1981) a few decades ago, it became clear that beat-by-beat oscillations in RR interval length (i.e. heart-rate variability [HRV]) contain information on underlying neural-control mechanisms based on the instantaneous balance between parasympathetic and sympathetic innervation. Over the years, the number of studies addressing HRV has increased markedly and now outnumbers 23,000. Despite such a large interest, there is still a continuing debate about interpretation of indices produced by computer analysis of HRV.The main part of studies relies on spectral techniques to extract parameters that are linked to hidden information. The general idea is that these proxies of autonomic regulation can be useful to clinical applications in various conditions in which autonomic dysregulation may play a role. There are, however, serious shortcomings related to algorithms, interpretation, and the hidden value of individual indices. In particular, it appears that specific training is necessary to interpret the hidden informational value of HRV. This technical complexity represents a severe barrier to large-scale clinical applications. Moreover, important differences in HRV separate the sexes, and age plays an additional confounding role.We present here a preliminary application of a novel unitary index of RR variability (Autonomic Nervous System Index of cardiac regulation) capable of providing information on the performance of autonomic regulation using a percentile rank position as projected on a large benchmark population. A summary of the underlying sympatho-vagal model is also presented.

Background: Long term endurance training, as occurring in elite athletes, is associated to cardiac neural remodeling in favor of cardioprotective vagal mechanisms, resulting in resting bradycardia and augmented contribution of cardiac parasympathetic nerve activity. Autonomic assessment can be performed by way of heart rate variability. This technique however provides multiple indices, and there is not yet complete agreement on their specific significance. Purpose of the study was to assess whether a rank transformation and radar plot could provide a unitary autonomic index, capable to show a correlation between intensity of individual work and quality of autonomic regulation., Methods: We studied 711 (23.6±6.2 years) elite athletes that took part in the selection procedure for the 2016 Rio Olympic Games for the National Italian Olympic Committee (CONI). Indices from Heart Rate Variability HRV obtained at rest, during standing up and during recovery from an exercise test were used to compute a percent ranked unitary autonomic index for sport (ANSIs), taken as proxy of quality of autonomic regulation., Results: Within the observed wide range of energy expenditure, the unitary autonomic index ANSIs appears significantly correlated to individual and discipline specific training workloads (r=0.25, P<0.001 and r=0.78, P<0.001, respectively), correcting for possible age and gender bias. ANSIs also positively correlates to lipid profile., Conclusions: Estimated intensity of physical activity correlates with quality of cardiac autonomic regulation, as expressed by a novel unitary index of cardiac autonomic regulation. ANSIs could provide a novel and convenient approach to individual autonomic evaluation in athletes.

Objective: The optimal protein intake for elderly individuals who exercise regularly has not yet been clearly defined. The aim of this study was to test the hypothesis that protein intake level is associated with muscle strength in elderly elite athletes., Methods: We evaluated 50 elite senior athletes (38 men and 12 women) participating in the European Master Games 2011 in an observational cross-sectional study. Participants were divided into two groups-lower (LPI) or higher (HPI) protein intake-according to the median value of their ratio of urinary urea nitrogen to urinary creatinine (i.e., 8.8 g/L), as a marker of protein intake. A dietary interview confirmed differences in protein consumption between the LPI and HPI groups. We also evaluated body composition (bioimpedance), muscle strength, and hematochemical indices., Results: LPI and HPI groups were homogeneous for age (72 [68-74] and 71 [68-74] y, respectively), fat-free mass index (18.4 [17-19.4] and 18.2 [17-19.1] kg/m 2 ), body fat (18.3% [12.3-20.7%] and 16.6% [13.6-21.2%]), and glomerular filtration rate (57.7 [53.8-64.9] and 62.7 [56.1-69.3] mL/min/1.73 m 2 ). The HPI group showed greater leg and trunk muscle strength (N) compared with the LPI group (left leg extension, 339 [238-369] versus 454 [273-561], respectively, P < 0.05; right leg extension, 319 [249-417] versus 432 [334-635], P ≤ 0.05; trunk extension, 435 [370-467] versus 464 [390-568], P ≤ 0.05)., Conclusions: Higher protein intake in elite senior athletes is associated with a greater muscle strength., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Spectral analysis of Heart Rate Variability (HRV) is a simple, non-invasive technique that is widely used in sport to assess sympatho-vagal regulation of the heart. Its employment is increasing partly due to the rising usage of wearable devices. However data acquisition using these devices may be suboptimal because they cannot discriminate between sinus and non-sinus beats and do not record any data regarding respiratory frequency. This information is mandatory for a correct clinical interpretation., Methods: This study involved 974 elite athletes, all of them underwent a complete autonomic assessment, by way of Autoregressive HRV analysis., Results: In 91 subjects (9% of the total population) we observed criticalities of either cardiac rhythm or respiration. Through perusal of one-lead ECG analysis we observed that 77 subjects had atrial or ventricular ectopy, i.e. conditions which impair stationarity and sinus rhythm. Running anyway autonomic nervous system analysis in this population, we observed that RR variance and raw values of LF and HF regions are significantly higher in arrhythmic subjects. In addition 14 subjects had slow (about 6 breath/min, 0.1Hz) respiration. This condition clouds the separation between LF from HF spectral regions of RR interval variability, respectively markers of the prevalent sympathetic and vagal modulation of SA node and of their synergistic interaction., Conclusions: Caution must be payed when assessing HRV with non-ECG wearable devices. Recording ECG signal and ensuring that respiratory rate is higher than 10 breath/min are both prerequisites for a more reliable analysis of HRV particularly in athletes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The study proposes an extension of cardiac baroreflex (cBR) sequence analysis, traditionally performed over spontaneous fluctuations of heart period and systolic arterial pressure, to typify peripheral resistance baroreflex (prBR) from spontaneous variations of peripheral resistances and diastolic arterial pressure. The prBR baroreflex sensitivity (BRS prBR ) and percentage of prBR sequences (SEQ% prBR ) were computed along with analogous quantities assessed over cBR (i.e. BRS cBR and SEQ% cBR ). The cBR and prBR were typified in healthy subjects at rest (REST) and during light bicycle ergometer exercise at 10 percent of the maximal effort (EXE). Both cBR and prBR were affected by EXE: indeed, BRS cBR and SEQ% prBR were significantly reduced. Moreover, while BRS cBR and BRS prBR were not significantly associated, SEQ% cBR and SEQ% prBR were, and the correlation coefficient was positive. This study suggests that prBR can be typified from spontaneous variabilities along with the more traditional cBR, thus enlarging the possibility of monitoring human cardiovascular control mechanisms.

Background: This study addresses whether a unitary cardiac autonomic nervous system index (ANSI), obtained combining multiple metrics from heart rate variability (HRV) into a radar plot could provide an easy appreciation of autonomic performance in a clinical setting., Materials and Methods: Data are standardized using percentile ranking of autonomic proxies from a relatively large reference population (n = 1593, age 39 ± 13 years). Autonomic indices are obtained from autoregressive spectral analysis of (ECG derived) HRV at rest and during standing up. A reduced ANSI (using RR, RR variance and rest-stand difference of LFnu) is then constructed as a radar plot, quantified according to its combined area and tested against different risk subgroups., Results: With growing risk profile, there is a marked reduction of the rank value of ANSI, quantified individually by the radar plot area. The practical usefulness of the approach was tested in small groups of additional subjects putatively characterized by elevated or poor autonomic performance. Data show that elite endurance athletes are characterized by elevated values of ANSI (80·6 ± 14·9, P < 0·001) while subjects with either Type 1 or Type 2 diabetes show lower values (DM1 = 37·0 ± 18·9 and DM2 = 26·8 ± 23·3, P = 0·002), and patients with coronary artery disease (CAD) represent a nadir (17 ± 20, P < 0·001)., Conclusions: This observational study shows the feasibility of testing simpler metrics of cardiac autonomic regulation based on a multivariate unitary index in a preventive setting. This simple approach might foster a wider application of HRV in the clinical arena, and permit an easier appreciation of autonomic performance., (© 2017 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: In the general population higher levels of exercise capacity seem to protect the cardiovascular system with effects well beyond traditional risk factors. We hypothesize that this phenomenon, called "risk factor gap", could be ascribed to functional components, such as autonomic adaptation to aerobic training., Methods: In 257 subjects (age 36.2±0.8 years) we measured VO2peak (incremental cycling exercise), together with arterial pressure and autonomic proxies (baroreflex gain, R-R variance and standing induced increase in marker of excitatory oscillatory regulation of the SA node, ∆LFRRnu)., Results: Autonomic proxies appeared significantly correlated with indicators of aerobic fitness (age and gender corrected correlation between VO2peak, baroreflex gain: r=0.277, P<0.001, and DAP r=-0.228, P<0.001). Subsequently, subjects were subdivided in three age and gender adjusted categories of VO2peak (poor, medium and good). Autonomic indices and arterial pressure appeared significantly ordered with categories of VO2peak (P<0.006). In addition, within these categories the proportion of subjects with a desirable autonomic and pressure profile becomes significantly greater with better fitness levels., Conclusions: The strong ordered relationship between categories of aerobic fitness and autonomic proxies speaks in favor of a complementary role of the autonomic nervous system in the management of cardiovascular risk factor gap at a population level.

Purpose: Autonomic assessment might be useful in training management. We planned to assess whether oscillatory metrics of RR variability (such as LFnu) would be more efficient than static indices from low order statistics (RR variance) at discriminating laying rest from stand posture, as an analog of a shift to sympathetic dominance., Methods: We studied a large population of elite Olympic athletes: a total of 406 athletes (162 females and 244 males, of similar age 21.7 and 24.4 years) participating to the selection for the upcoming 2016 Olympic games. We employed various methods to extract autonomic indices from RR variability and employed a stepwise statistical approach combining factor and discriminant analysis., Results: We observed that that relative power of oscillatory components from spectral analysis of RR variability (such as LF or HF in nu) and indices from symbolic analysis (particularly 0V) clearly outperform RR variance in discriminating between two physiological conditions (laying rest and stand) related to posture and autonomic activation., Conclusions: In world class Olympic athletes we have shown that a small subset of RR variability indices, related to sympathovagal balance, may be more appropriate than RR variance to assess excitatory sympathetic autonomic responsiveness of the SA node. These findings may have practical implications for the use of RR variability in guiding training and predicting success in competitions.

Aim: Given the time spent at work, the workplace represents an ideal setting to implement preventive programs for non-communicable diseases, the major cause of mortality and morbidity in Western and developing countries. We sought to verify if an ecological approach based on corporate culture, employees' education and concrete modifications of workplace environment, offering easy opportunity to assume healthy lifestyle, could be associated with reduced cardiometabolic risk., Methods: The study involved 1089 workers in two multinational companies following different workplace health promotion policies. Company A offered to all employees the opportunity to access a web platform dedicated to general information on health and diseases. Company B implemented an ecological model encompassing company culture, employees' education and concrete modifications of workplace environment, giving to all employees the opportunity to adopt healthy solutions throughout daily living at workplace. Participants volunteered self-reported clinical information using an IT tool. Numbers of Metabolic Syndrome components (MetS) were taken as proxy of cardiometabolic risk., Results: MetS probability obtained via statistical modeling was lower in company B as compared to company A, and absenteeism was also lower in company B. Our study shows that a work environment favoring assumption of healthy lifestyle, as in company B, is associated with a lower percentage of employees with MetS components and lower absenteeism. Moreover, statistical modeling shows that individual probabilities of being without MetS elements, controlling for age and gender, is remarkably higher in company B., Conclusions: Our data suggest that ecological approaches might be useful in worksite prevention policies.

Purpose: Surgery and adjuvant therapy improved prognosis of breast cancer survivors. This improvement risks being offset by potential late-occurring cardiovascular toxicity of oncologic treatment and increased cardiometabolic risk profile associated with lifestyle changes. We address the hypothesis that in breast cancer survivors, multiple functional alterations might define a phenotype, characterized by vagal impairment, diminished aerobic fitness, increased metabolic risk, and reduced wellbeing., Methods: We studied 171 sedentary asymptomatic women (106 cancer survivor-65 controls) of similar age (53 ± 8.6; 51 ± 8.1 years). Autonomic regulation was evaluated by autoregressive spectral analysis of R wave to R wave (RR) interval and systolic arterial pressure variability. Aerobic fitness was directly assessed by cardiopulmonary exercise test. Body mass index (BMI) and waist circumference served as proxies of metabolism. Fatigue and stress-related symptoms were evaluated with validated questionnaire., Results: Patients showed significantly smaller total RR variance (1644 ± 2363 vs. 2302 ± 1561 msec2), smaller absolute power of low frequency (LF) (386 ± 745 vs. 810 ± 1300 msec2) and high frequency (HF) (485 ± 1202 vs. 582 ± 555 msec2) of RR interval variability and smaller spontaneous baroreflex sensitivity (15.0 ± 8.9 vs. 21.9 ± 10 msec/mmHg), suggesting vagal impairment. VO2 peak and O2 pulse were lower in cancer survivors than in controls. Fatigue and stress-related somatic symptoms scores were higher, as was BMI and waist circumference., Conclusion: Breast cancer survivors show multiple dysfunctions: vagal impairment, lower aerobic fitness, signs of altered metabolism, and higher perception of fatigue., Implications for Cancer Survivors: We propose that the concept of clinical phenotype, which may accommodate multiple functional disturbances, might be useful in long-term personalized prevention programs for breast cancer survivors.