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Previous studies showed that transcutaneous vagus nerve stimulation (tVNS) modulates the autonomic nervous system (ANS) in resting condition. However, the autonomic regulation in response to an orthostatic challenge during tVNS in healthy subjects remains unknown. We tested the hypothesis that tVNS reduces heart rate (HR) and alters the responsivity of ANS to orthostatic stress in healthy subjects. In a randomized and cross-over trial, thirteen healthy subjects underwent two experimental sessions on different days: (1) tVNS and (2) control. Using a tVNS device, an auricular electrode was placed on the left cymba conchae of the external ear; an electric current with a pulse frequency of 25 Hz and amplitude between 1 and 6 mA was applied. For the assessment of ANS, the beat-to-beat HR and systolic arterial pressure (SAP) were analyzed using linear and nonlinear approaches during clinostatic and orthostatic conditions. In clinostatic conditions, tVNS reduced HR ( p < 0.01), SAP variability ( p < 0.01), and cardiac and peripheral sympathetic modulation ( p < 0.01). The responsivity of the peripheral sympathetic modulation to orthostatic stress during tVNS was significantly higher when compared to the control session ( p = 0.03). In conclusion, tVNS reduces the HR and affects cardiac and peripheral autonomic control and increases the responses of peripheral autonomic control to orthostatic stress in healthy subjects.

Short sleep duration has a substantial influence on the overall health of an individual. Short sleep time can be a consequence of lifestyle habits, environmental factors, or the presence of a sleep disorder, such as insomnia or sleep-disordered breathing. Short sleep time is associated with increased morbidity and mortality, mainly from cardiovascular disorders (including coronary artery disease, arrhythmias, and hypertension). Several biological mechanisms have been proposed as a possible link between short sleep duration and these diseases, such as involvement of the autonomic nervous system, endothelial function, metabolic regulation, inflammation, and the coagulation system. In this Review, we provide an overview on the effects of short sleep duration on cardiovascular health and diseases and discuss the main pathophysiological mechanisms involved, taking into account both experimental data and clinical evidence.

The aim of our study is to compare patent foramen ovale (PFO) closure versus medical treatment and antiplatelet versus anticoagulant therapy in patients with cryptogenic stroke (CS) and PFO. We conducted a systematic review and meta-analysis with trial sequential analysis (TSA) of randomized trials. Primary outcomes are stroke or transient ischemic attack (TIA) and all-cause mortality. Secondary outcomes are peripheral embolism, bleeding, serious adverse events, myocardial infarction and atrial dysrhythmias. We performed an intention to treat meta-analysis with a random-effects model. We include six trials (3677 patients, mean age 47.3 years, 55.8% men). PFO closure is associated with a lower recurrence of stroke or TIA at a mean follow-up of 3.88 years compared to medical therapy [risk ratio (RR) 0.55, 95% CI 0.38-0.81; I 2  = 40%]. The TSA confirms this result. No difference is found in mortality (RR 0.74, 95% CI 0.35-1.60; I 2  = 0%), while PFO closure is associated with a higher incidence of atrial dysrhythmias (RR 4.55, 95% CI 2.16-9.60; I 2  = 25%). The rate of the other outcomes is not different among the two groups. The comparison between anticoagulant and antiplatelet therapy shows no difference in terms of stroke recurrence, mortality and bleeding. There is conclusive evidence that PFO closure reduces the recurrence of stroke or TIA in patients younger than 60 years of age with CS. More data are warranted to assess the consequences of the increase in atrial dysrhythmias and the advantage of PFO closure over anticoagulants.

Controlled breathing maneuver is being widely applied for cardiovascular autonomic control evaluation and cardiac vagal activation through reduction of breathing rate (BR). However, this maneuver presented contradictory results depending on the protocol and the chosen BR. These variations may be related to the individual intrinsic profile baseline sympathetic tonus, as described before by others. In this study, we evaluated the effect of controlled breathing maneuver on cardiovascular autonomic control in 26 healthy subjects allocated into two protocols: (1) controlled breathing in three different rates (10, 15, and 20 breaths/min) and (2) controlled breathing in rates normalized by the individual spontaneous breathing rate (SBR) at 100, 80, 70, and 50%. Our results showed autonomic responses favorable to vagal modulation with the lower BR maneuvers. Nevertheless, while this activation was variable using the standard protocol, all participants of the normalized protocol demonstrated an increase of vagal modulation at 80% BR (HFnu 80 = 67.5% vs. 48.2%, p < 0.0001). These results suggest that controlled breathing protocols to induce vagal activation should consider the SBR, being limited to values moderately lower than the baseline.

Objectives: Patients with chronic disorders of consciousness (DOC) may show alterations of autonomic function; however, in this clinical population, no data are available on the specific effects of nociceptive stimuli on cardiac autonomic control. Thus, we aimed at investigating the effects of a noxious stimulation on heart rate variability (HRV) in a population of patients with chronic DOC, taking into account different states of consciousness (vegetative state/unresponsive wakefulness syndrome, VS/UWS and minimally conscious state, MCS)., Methods: We enrolled twenty-four DOC patients (VS/UWS, n = 12 and MCS, n = 12). ECG and respiration were recorded during baseline, immediately after the nociceptive stimulus and, finally, during the recovery period. Linear and nonlinear HRV measures were used to evaluate the cardiac autonomic control., Results: In DOC patients, nonlinear HRV analysis showed that nociceptive stimuli are able to elicit a change of autonomic function characterized by an increased sympathetic and a reduced vagal modulation. A significant reduction of autonomic complexity has also been detected. More interestingly, VS/UWS patients showed a less complex dynamics compared to MCS patients., Conclusions: Cardiac autonomic responses are able to significantly differentiate the autonomic function between VS/UWS and MCS patients., Significance: Nonlinear HRV analysis may represent a useful tool to characterize the cardiac autonomic responses to nociceptive stimuli in a chronic DOC population., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Aims: Air particulate matter (PM) is associated with increased cardiovascular morbidity and mortality. Altered autonomic functions play a key role in PM-induced cardiovascular disease. However, previous studies have not address the impact of PM on sympathetic and parasympathetic control of heart function, independently, and using controlled conditions, i.e., increasing titration of PM of known composition, in absence of other potential confounding factors. To fill this gap, here we used symbolic analysis that is capable of detecting non-mutual changes of the two autonomic branches, thus considering them as independent, and concentrations of PM as they could be measured at peak levels in Milan during a polluted winter day., Methods and Results: In this randomized, cross-over study, we enrolled 12 healthy subjects who underwent two random sessions: inhalation of filtered air mixture or inhalation of filtered air containing particulate mixture (PM 10, PM 2.5, PM 1.0 and PM 0.5µm). ECG and respiration for autonomic analysis and blood sample for DNA Methylation were collected at baseline (T1), after air exposure (T2) and after 2h (T3). Spectral and symbolic analysis of heart rate variability (HRV) were performed for autonomic control of cardiac function, while alterations in DNA methylation of candidate genes were used to index pro-inflammatory modifications. In the PM expose group, autonomic analysis revealed a significant decrease of 2UV%, index of parasympathetic modulation (14% vs 9%, p = 0.0309), while DNA analysis showed a significant increase of interferon γ (IFN- γ) methylation, from T1 to T3. In a mixed model using T1, T2 and T3, fine and ultrafine PM fractions showed significant associations with IFN- γ methylation and parasympathetic modulation., Conclusions: Our study shows, for the first time, that in healthy subjects, acute exposure to PM affects parasympathetic control of heart function and it increases methylation of a pro-inflammatory gene (i.e. methylation of interferon γ). Thus, our study suggests that, even in absence of other co-factors and in otherwise healthy individuals, PM per se is sufficient to trigger parasympathetic dysautonomia, independently from changes in sympathetic control, and inflammation, in a dose-dependent manner., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Attacks of Hereditary Angioedema due to C1-inhibitor deficiency (C1-INH-HAE)are often triggered by stressful events/hormonal changes., Objective: Our study evaluates the relationship between autonomic nervous system (ANS) and contact/complement system activation., Methods: Twenty-three HAE patients (6 males, mean age 47.5±11.4 years) during remission and 24 healthy controls (8 males, mean age 45.3±10.6 years) were studied. ECG, beat-by-beat blood pressure, respiratory activity were continuously recorded during rest (10') and 75-degrees-head-up tilt (10'). C1-INH, C4, cleaved high molecular weight kininogen (cHK) were assessed; in 16 patients and 11 controls plasma catecholamines were also evaluated. Spectral analysis of heart rate variability allowed extraction of low-(LF) and high-(HF) frequency components, markers of sympathetic and vagal modulation respectively., Results: HAE patients showed higher mean systolic arterial pressure (SAP) than controls during both rest and tilt. Tilt induced a significant increase in SAP and its variability only in controls. Although sympathetic modulation (LFnu) increased significantly with tilt in both groups, LF/HF ratio, index of sympathovagal balance, increased significantly only in controls. At rest HAE patients showed higher noradrenaline values (301.4±132.9 pg/ml vs 210.5±89.6pg/ml, p = 0.05). Moreover, in patients tilt was associated with a significant increase in cHK, marker of contact system activation (49.5 ± 7.5% after T vs 47.1 ± 7.8% at R, p = 0.01)., Conclusions: Our data are consistent with altered ANS modulation in HAE patients, i.e. increased sympathetic activation at rest and blunted response to orthostatic challenge. Tilt test-induced increased HK cleavage suggests a link between stress and bradykinin production.

Objective: Myotonic dystrophy type 1 (DM1) is a hereditary myopathy characterized by an autosomal dominant inheritance with important cardiovascular and autonomic deregulation. DM1 patients have a high prevalence of obstructive sleep apnea (OSA), but the effects of this comorbidity on cardiovascular autonomic control (CAC) are unknown. The present study aimed to investigate CAC during sleep-wake cycle in DM1 patients, taking into account the effects of OSA comorbidity., Method: Twenty-three patients with a diagnosis of DM1, and a control group, underwent a complete polysomnographic study (PSG). Electrocardiogram and respiration were extracted from PSG, divided according to the sleep stages, and analyzed using spectral analysis (SpA) of heart rate variability (HRV). SpA identified three components: very low frequency (VLF), low frequency (LF), a marker of sympathetic modulation, and high frequency (HF), a marker of vagal modulation., Results: The results showed that in DM1 patients, the sympathovagal balance shifted towards a vagal predominance during non-rapid eye movement (NREM) sleep and a sympathetic predominance during rapid eye movement (REM) sleep. Second, this preserved cardiac autonomic modulation was not affected by the comorbidity with obstructive sleep apnea syndrome (OSAS). Third, in DM1 patients, OSAS comorbidity was associated with a reduction in HRV during the whole sleep-wake cycle. Lastly, in DM1 patients with OSA, cardiorespiratory coupling was reduced compared to controls., Conclusions: DM1 patients had preserved cardiac autonomic dynamics during NREM and REM sleep, and this phenomenon was not affected by the presence of OSA. However, the comorbidity with OSA was characterized by a reduction in total HRV, which is a marker of the ability of autonomic control to respond to stressors stimuli., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Several studies have demonstrated that adjuvant therapies as exercise and breathing training are effective in improving cardiac autonomic control (CAC) in patients with affective spectrum disorders. However, the effects of Sudarshan Kriya Yoga (SKY) on autonomic function in this population is unknown. Our objective was to test the hypothesis that SKY training improves CAC and cardiorespiratory coupling in patients with anxiety and/or depression disorders., Methods: Forty-six patients with a diagnosis of anxiety and/or depression disorders (DSM-IV) were consecutively enrolled and divided in two groups: 1) conventional therapy (Control) and 2) conventional therapy associated with SKY (Treatment) for 15 days. Anxiety and depression levels were determined using quantitative questionnaires. For the assessment of CAC and cardiorespiratory coupling, cardiorespiratory traces were analyzed using monovariate and bivariate autoregressive spectral analysis, respectively., Results: After 15-days, we observed a reduction of anxiety and depression levels only in Treatment group. Moreover, sympathetic modulation and CAC were significantly lower while parasympathetic modulation and cardiorespiratory coupling were significantly higher in the Treatment compared to Control group., Conclusions: Intensive breathing training using SKY approach improves anxiety and/or depressive disorders as well as CAC and cardiorespiratory coupling. These finding suggest that the SKY training may be a useful non-pharmacological intervention to improve symptoms and reduce cardiovascular risk in patients with anxiety/depression disorders., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Acute sleep deprivation (SD) alters cardiovascular autonomic control (CAC) and is associated with an increased risk of cardiovascular disorders. However, the effects of partial SD on CAC are unclear. Thus, we aimed to investigate the effects of partial SD on CAC during sleep. We randomized seventeen healthy subjects to a restriction group (RES, n  = 8, subjects slept two-thirds of normal sleep time based on individual habitual sleep duration for 8 days and 8 nights) or a Control group (CON, n  = 9, subjects were allowed to sleep their usual sleep time). Attended polysomnographic (PSG) studies were performed every night; a subset of them was selected for the analysis at baseline (day 3-D3), the first night after sleep restriction (day 5-D5), at the end of sleep restriction period (day 11-D11), and at the end of recovery phase (day 14-D14). We extracted electrocardiogram (ECG) and respiration from the PSG and divided into wakefulness (W), nonrapid eye movements (REM) sleep (N2 and N3) and REM sleep. CAC was evaluated by means of linear spectral analysis, nonlinear symbolic analysis and complexity indexes. In both RES and CON groups, sympathetic modulation decreased and parasympathetic modulation increased during N2 and N3 compared to W and REM at D3, D5, D11, D14. Complexity analysis revealed a reduction in complexity during REM compared to NREM sleep in both DEP and CON After 8 days of moderate SD, cardiac autonomic dynamics, characterized by decreased sympathetic, and increased parasympathetic modulation, and higher cardiac complexity during NREM sleep, compared to W and REM, are preserved., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

To evaluate whether captopril (3×50 mg/day) potentiates post-resistance exercise hypotension (PREH) in hypertensives (HT), 12 HT men received captopril and placebo for 4 weeks each in a double-blinded, randomized-crossover design. On each therapy, subjects underwent 2 sessions: Control (C - rest) and Resistance Exercise (RE - 7 exercises, 3 sets to moderate fatigue, 50% of 1 RM -repetition maximum). Measurements were taken before and after 30-60 min (Post1) and 7 h (Post2), and ambulatory blood pressure (BP) was monitored for 24 h. There were no differences in PREH characteristics and mechanisms between the placebo and captopril periods. At Post1, systolic/diastolic BP decreased significantly and similarly after RE with both therapies (Placebo=-13±2/-9±1 mmHg vs. Captopril=-12±2/-10±1 mmHg, P<0.05). RE reduced cardiac output in some subjects and systemic vascular resistance in others. Heart rate and cardiac sympathetic modulation increased, while stroke volume and baroreflex sensitivity decreased after RE (Placebo: +13±2 bpm, +21±5 nu, -11±5 ml, -4±2 ms/mmHg; Captopril: +13±2 bpm, +35±4 nu, 17±5 ml, -3±1 ms/mmHg, P<0.05). At Post2, all variables returned to pre-intervention values. Ambulatory BP was similar between the sessions. Thus, captopril did not potentiate the magnitude and duration of PREH in HT men, and it did not influence PREH mechanisms., (© Georg Thieme Verlag KG Stuttgart · New York.)

Heart failure (HF) is a complex syndrome representing the clinical endpoint of many cardiovascular diseases of different etiology. Given its prevalence, incidence and social impact, a better understanding of HF pathophysiology is paramount to implement more effective anti-HF therapies. Based on left ventricle (LV) performance, HF is currently classified as follows: (1) with reduced ejection fraction (HFrEF); (2) with mid-range EF (HFmrEF); and (3) with preserved EF (HFpEF). A central tenet of HFrEF pathophysiology is adrenergic hyperactivity, featuring increased sympathetic nerve discharge and a progressive loss of rhythmical sympathetic oscillations. The role of reflex mechanisms in sustaining adrenergic abnormalities during HFrEF is increasingly well appreciated and delineated. However, the same cannot be said for patients affected by HFpEF or HFmrEF, whom also present with autonomic dysfunction. Neural mechanisms of cardiovascular regulation act as "controller units," detecting and adjusting for changes in arterial blood pressure, blood volume, and arterial concentrations of oxygen, carbon dioxide and pH, as well as for humoral factors eventually released after myocardial (or other tissue) ischemia. They do so on a beat-to-beat basis. The central dynamic integration of all these afferent signals ensures homeostasis, at rest and during states of physiological or pathophysiological stress. Thus, the net result of information gathered by each controller unit is transmitted by the autonomic branch using two different codes: intensity and rhythm of sympathetic discharges. The main scope of the present article is to (i) review the key neural mechanisms involved in cardiovascular regulation; (ii) discuss how their dysfunction accounts for the hyperadrenergic state present in certain forms of HF; and (iii) summarize how sympathetic efferent traffic reveal central integration among autonomic mechanisms under physiological and pathological conditions, with a special emphasis on pathophysiological characteristics of HF.

Sleep deprivation (SD) has become a relevant health problem in modern societies. We can be sleep deprived due to lifestyle habits or due to sleep disorders, such as insomnia, obstructive sleep apnea (OSA) and neurological disorders. One of the common element of sleep disorders is the condition of chronic SD, which has complex biological consequences. SD is capable of inducing different biological effects, such as neural autonomic control changes, increased oxidative stress, altered inflammatory and coagulatory responses and accelerated atherosclerosis. All these mechanisms links SD and cardiovascular and metabolic disorders. Epidemiological studies have shown that short sleep duration is associated with increased incidence of cardiovascular diseases, such as coronary artery disease, hypertension, arrhythmias, diabetes and obesity, after adjustment for socioeconomic and demographic risk factors and comorbidities. Thus, an early assessment of a condition of SD and its treatment is clinically relevant to prevent the harmful consequences of a very common condition in adult population., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A low resting heart rate (HR) would be of great benefit in cardiovascular diseases. Ivabradine-a novel selective inhibitor of hyperpolarization-activated cyclic nucleotide gated (HCN) channels- has emerged as a promising HR lowering drug. Its effects on the autonomic HR control are little known. This study assessed the effects of chronic treatment with ivabradine on the modulatory, reflex and tonic cardiovascular autonomic control and on the renal sympathetic nerve activity (RSNA). Male Wistar rats were divided in 2 groups, receiving intraperitoneal injections of vehicle (VEH) or ivabradine (IVA) during 7 or 8 consecutive days. Rats were submitted to vessels cannulation to perform arterial blood pressure (AP) and HR recordings in freely moving rats. Time series of resting pulse interval and systolic AP were used to measure cardiovascular variability parameters. We also assessed the baroreflex, chemoreflex and the Bezold-Jarish reflex sensitivities. To better evaluate the effects of ivabradine on the autonomic control of the heart, we performed sympathetic and vagal autonomic blockade. As expected, ivabradine-treated rats showed a lower resting (VEH: 362 ± 16 bpm vs. IVA: 260 ± 14 bpm, p = 0.0005) and intrinsic HR (VEH: 369 ± 9 bpm vs. IVA: 326 ± 11 bpm, p = 0.0146). However, the chronic treatment with ivabradine did not change normalized HR spectral parameters LF (nu) (VEH: 24.2 ± 4.6 vs. IVA: 29.8 ± 6.4; p > 0.05); HF (nu) (VEH: 75.1 ± 3.7 vs. IVA: 69.2 ± 5.8; p > 0.05), any cardiovascular reflexes, neither the tonic autonomic control of the HR (tonic sympathovagal index; VEH: 0.91± 0.02 vs. IVA: 0.88 ± 0.03, p = 0.3494). We performed the AP, HR and RSNA recordings in urethane-anesthetized rats. The chronic treatment with ivabradine reduced the resting HR (VEH: 364 ± 12 bpm vs. IVA: 207 ± 11 bpm, p < 0.0001), without affecting RSNA (VEH: 117 ± 16 vs. IVA: 120 ± 9 spikes/s, p = 0.9100) and mean arterial pressure (VEH: 70 ± 4 vs. IVA: 77 ± 6 mmHg, p = 0.3293). Our results suggest that, in health rats, the long-term treatment with ivabradine directly reduces the HR without changing the RSNA modulation and the reflex and tonic autonomic control of the heart.

Aim: Reflex alterations of cardiac autonomic modulation have been described after acute myocardial infarction (AMI). The non-homogeneous autonomic innervation of the heart gives reason of different patterns of autonomic modulation depending upon the site of AMI. Conflicting data are available on cardiac autonomic modifications after primary percutaneous coronary intervention (pPCI). We evaluated cardiac autonomic changes in patients with ST-elevation myocardial infarction (STEMI) after pPCI, either within 24h after revascularization (T0) and at clinical stability (T1, 6±2days), taking into account the site of infarction., Methods and Results: We enrolled 33 consecutive patients with STEMI treated with pPCI (25 males, mean age 61±12.1yr); 15 had an anterior wall STEMI (ANT) and 18 had an inferior wall STEMI (INF). ECG and respiration were recorded at T0 and at T1. Cardiac autonomic modulation was evaluated by means of symbolic analysis of heart rate variability. At T0, At T0, 0V% (marker of sympathetic modulation) was higher in INF compared to ANT [31% (18-43) vs 18% (7-32), p=0.014]. Moreover, ANT had a higher 2LV%, index of vagal modulation, compared to INF [8% (7-15) vs 5% (2-8), p=0.006]., Conclusion: After pPCI, these preliminary results suggest that patients with INF were characterized by a sympathetic predominance, while ANT by a predominant vagal modulation. Our data suggest that pPCI can be associated with specific autonomic patterns, which are different for ANT and INF STEMI, according to the different autonomic innervation. Future ad hoc studies are needed to confirm these preliminary observations., (Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Spinal cord injuries (SCI) are associated with altered cardiovascular autonomic control (CAC). Sleep is characterized by modifications of autonomic control across sleep stages; however, no data are available in SCI subjects on CAC during sleep. We aim to assess cardiac autonomic modulation during sleep in subjects with SCI., Patients and Methods: 27 participants with a neurological and radiological diagnosis of cervical (Cerv, n = 12, ie, tetraplegic) and thoracic SCI (Thor, n = 15, ie, paraplegic) and healthy subjects (Controls) were enrolled. Overnight polysomnographic (PSG) recordings were obtained in all participants. Electrocardiography and respiration were extracted from PSG, divided into sleep stages [wakefulness (W), non-REM sleep (NREM) and REM] for assessment of CAC, using symbolic analysis (SA) and corrected conditional entropy (CCE). SA identified indices of sympathetic and parasympathetic modulation and CCE evaluated the degree of complexity of the heart period time series., Results: SA revealed a reduction of sympathetic and predominant parasympathetic control during NREM compared to W and REM in SCI patients, independent of the level of the lesion, similar to the Controls. In all three groups, complexity of autonomic regulation was higher in NREM compared to W and REM., Conclusions: In subjects with SCI, cardiac autonomic control changed across sleep stages, with a reduction of sympathetic and an increase of parasympathetic modulation during NREM compared to W and REM, and a parallel increase of complexity during NREM, which was similar to the Controls. Cardiac autonomic dynamics during sleep are maintained in SCI, independent of the level of the lesion., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective/background: Major cardiovascular events frequently increase in the morning due to abrupt changes in the sympatho-vagal cardiac control during the transition from sleep to wakefulness. These neural changes are translated into stepwise increases in cardiac functions, resulting in a potential cardiovascular stress. Here, we explored whether light can "optimize" heart rate and its neural control, by actively promoting a less steep transition from sleep to wakefulness, thus minimizing morning cardiovascular vulnerability., Methods: Seventeen healthy young men were awakened 2-hours before their habitual wake-time. In a counterbalanced within-subject design, we applied a control condition (darkness during sleep and dim light during wakefulness) or dawn-simulation-light (DSL) starting 30-minutes before and ending 30-minutes after scheduled wake-up time., Results: Our data reveal a significantly gradient reduction in heart rate during the transition from sleep to wakefulness, when applying DSL as compared to a control condition. Likewise, cardiac sympatho-vagal control smoothly increased throughout the 30-min sleep episode preceding scheduled wake-up under DSL and remained stable for the first 30-min of wakefulness. Interestingly, these effects were mostly driven by changes in the parasympathetic cardiac control., Conclusions: Our data demonstrate for the first time that a non-invasive strategy, as light exposure surrounding the wake-up process, can significantly reduce the deleterious sleep-to-wake evoked cardiac modulation in healthy young men awakened under conditions of increased sleep pressure. A translational approach of this light exposure, which closely resembles natural lighting conditions in the morning, may therefore act as a potential protector for cardiac vulnerability in the critical morning hours., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Syncope may be the final common presentation of a number of clinical conditions spanning benign (i.e. neurally-mediated syncope) to life-threatening diseases (i.e. cardiac syncope). Hospitalization rate after a syncopal episode is high. An effective risk stratification is crucial to identify patients at risk of poor prognosis in the short term period to avoid unnecessary hospital admissions. The decision to admit or discharge a syncope patient from the ED is often based on the physician's clinical judgment. In recent years, several prognostic tools (i.e. clinical prediction rules and risk scores) have been developed to provide emergency physicians with accurate guidelines for hospital admission. At present, there are no compelling evidence that prognostic tools perform better than physician's clinical judgment in assessing the short-term outcome of syncope. However, the risk factors characterizing clinical prediction rules and risk scores may be profitably used by emergency doctors in their decision making, specifically whenever a syncope patient has to be discharged from ED or admitted to hospital. Patients with syncope of undetermined etiology, who are characterized by an intermediate-high risk profile after the initial evaluation, should be monitored in the ED. Indeed, data suggest that the 48h following syncope are at the highest risk for major adverse events. A new tool for syncope management is represented by the Syncope Unit in the ED or in an outpatient setting. Syncope Unit may reduce hospitalization and length of hospital stay. However, further studies are needed to clarify whether syncope patients' prognosis can be also improved., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Sleep is a fundamental physiological process, characterized by the activation of several cortical and subcortical neural networks. The relation between sleep and cardiovascular system is complex and bidirectional: sleep disorders may alter cardiovascular system, leading to an increased cardiovascular risk, while, on the contrary, cardio- vascular diseases are characterized by an alteration of physiological sleep. Autonomic nervous system (ANS) plays a key role in the regulation of cardiovascular functions during different sleep stages, with sympatho-vagal balance dynamically shifting towards sympathetic or vagal predominance across different sleep stages. Sleep deprivation (SD) has becoming one of the most relevant health problem in modern societies. SD can be related to aging, which is associated with increased sleep fragmentation, and to sleep disorders, such as sleep disordered breathing and neurological disorders. Experimental studies in animals showed that SD significantly affects cardiovascular functions, altering heart rate and blood pressure responses, and increasing sympathetic activity and neuroendocrine response to stressor stimuli. Clinical studies in humans have shown that SD, either due to experimental sleep loss and to sleep disorders, can affect different biological pathways, such as cardiovascular autonomic control, inflammation, immunity responses and metabolism. All these alterations may predispose subjects with SD to an increased cardiovascular risk. Hence, it is fundamental to identify the presence of a sleep disorder, which could be per se responsible for sleep loss, or the presence of sleep deprivation due to other factors, such as social life, habits etc., in order to identify subjects at high risk for cardiovascular events.

Background: A high prevalence of obstructive sleep apnea syndrome (OSAS) has been reported in severely obese patients with nonalcoholic fatty liver disease (NAFLD), but few studies have evaluated OSAS in non-morbidly obese NAFLD patients., Aims: To determine the prevalence of risk for OSAS with or without daytime sleepiness in non-morbidly obese patients with NAFLD and evaluate the association with the severity of liver damage., Methods: We considered 159 consecutive patients with histological NAFLD and body mass index (BMI) <35 Kg/m2, and 80 controls without ultrasonographic steatosis matched for age, sex, and BMI. OSAS risk was determined by positivity for Berlin questionnaire (BQ), and daytime sleepiness by the Sleepness Epworth Scale (ESS). Liver damage was evaluated according to the NAFLD activity score., Results: In NAFLD patients, BQ alone was positive in 39 (25%), ESS in 8 (5%), and both in 13 (8%, OSAS with sleepines); p = ns vs. controls without steatosis. In NAFLD patients at risk for OSAS with (but not in those without) sleepiness, we observed a higher prevalence of nonalcoholic steatohepatitis (NASH; 11/13, 85% vs. 72/146, 49%; p = 0.018), and of clinically significant fibrosis (stage>1; 9/13, 69% vs. 39/146, 27%; p = 0.003). At multivariate logistic regression analysis, OSAS with sleepiness was strongly associated with NASH and fibrosis>1 independently of known clinical risk factors such as age, gender, BMI, diabetes, and ALT levels (OR 7.1, 95% c.i. 1.7-51, p = 0.005 and OR 14.0, 95% c.i. 3.5-70, p = 0.0002, respectively)., Conclusions: A proportion of NAFLD patients without severe obesity is at risk for OSAS with daytime sleepiness, which is associated with the severity of liver damage independently of body mass and other cofactors.

Background: Treatment with positive airway pressure devices improved signs and symptoms of obstructive sleep apnea syndrome (OSA); however, auto-adjusting positive pressure (APAP) device was not as effective as continuous positive airway pressure (CPAP) in reducing arterial blood pressure and insulin resistance. The role played by autonomic cardiac regulation remains to be clarified. We aimed to test the effects of CPAP and APAP on autonomic regulation and cardiorespiratory coupling during sleep., Methods: We retrospectively analyzed full-night polysomnographic studies. 19 patients newly diagnosed with severe OSA (AHI>30) and 7 obese subjects without OSA (CON) were enrolled. Each OSA subject was assigned to CPAP or APAP treatment and underwent a sleep study after 1 week of treatment. Spectral and cross-spectral analyses of heart rate variability (HRV) and respiration were performed to assess autonomic profile and coherence (K2) between respiration and HF oscillation during sleep in CPAP, APAP and CON groups., Results: In CPAP and CON, LFnu and LF/HF, markers of sympathetic modulation, decreased from N2 to N3 and increased during REM sleep (p<0.001), while in APAP group, sympathetic modulation was significantly higher compared with those of CPAP and CON during all sleep stages. K2 values were lower in APAP compared with those in CPAP and CON., Conclusion: APAP treatment was characterized by a greater sympathetic activation and it was associated with a lower cardio-respiratory coupling compared with CPAP. This might account for the different effects on cardiovascular risk factors induced by the two treatments., (Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Sleep is a physiological process involving different biological systems, from molecular to organ level; its integrity is essential for maintaining health and homeostasis in human beings. Although in the past sleep has been considered a state of quiet, experimental and clinical evidences suggest a noteworthy activation of different biological systems during sleep. A key role is played by the autonomic nervous system (ANS), whose modulation regulates cardiovascular functions during sleep onset and different sleep stages. Therefore, an interest on the evaluation of autonomic cardiovascular control in health and disease is growing by means of linear and non-linear heart rate variability (HRV) analyses. The application of classical tools for ANS analysis, such as HRV during physiological sleep, showed that the rapid eye movement (REM) stage is characterized by a likely sympathetic predominance associated with a vagal withdrawal, while the opposite trend is observed during non-REM sleep. More recently, the use of non-linear tools, such as entropy-derived indices, have provided new insight on the cardiac autonomic regulation, revealing for instance changes in the cardiovascular complexity during REM sleep, supporting the hypothesis of a reduced capability of the cardiovascular system to deal with stress challenges. Interestingly, different HRV tools have been applied to characterize autonomic cardiac control in different pathological conditions, from neurological sleep disorders to sleep disordered breathing (SDB). In summary, linear and non-linear analysis of HRV are reliable approaches to assess changes of autonomic cardiac modulation during sleep both in health and diseases. The use of these tools could provide important information of clinical and prognostic relevance.

Aims: Brugada syndrome is characterized by typical ECG features, ventricular arrhythmias and sudden cardiac death (SCD), more frequent during nighttime. Autonomic cardiovascular control has been implicated in triggering the ventricular arrhythmias. Sleep-disordered breathing (SDB) elicits marked autonomic changes during sleep and is also associated with an increased risk of nighttime SCD. Brugada patients may have a higher likelihood of SDB compared to controls. However, no data are available on cardiac autonomic control in Brugada patients, particularly with regard to the comorbidity of SDB., Methods: We evaluated autonomic cardiovascular control in Brugada patients with SDB (BRU-SDB, n=9), without SDB (BRU, n=9), in controls (CON, n=8) and in non-Brugada patients with SDB (n=6), during wakefulness and sleep (N2, N3 and REM). Linear spectral and entropy-derived measures of heart rate variability (HRV) were performed during apnea-free stable breathing epochs., Results: Total HRV was attenuated in BRU-SDB compared to CON and BRU. During N2 and REM, in BRU-SDB patients sympathetic modulation decreased compared to BRU and CON, while during REM, they showed an increased parasympathetic modulation, compared to the other two groups. BRU-SDB and SDB were similar in terms of spectral components. Entropy-derived indices showed preserved dynamic changes in Brugada patients compared to controls through the different sleep stages., Conclusion: Brugada syndrome per se does not appear associated with an altered autonomic cardiovascular control during wakefulness and sleep. The comorbidity with SDB may contribute to disrupted autonomic cardiovascular regulation during sleep, possibly predisposing to the increased likelihood of sleep-related ventricular tachyarrhythmias and SCD., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Sleep loss is associated with increased cardiovascular morbidity and mortality. It is known that chronic sleep restriction affects autonomic cardiovascular control and inflammatory response. However, scanty data are available on the effects of acute sleep deprivation (ASD) due to night shifts on the cardiovascular system and its capability to respond to stressor stimuli. The aim of our study was to investigate whether a real life model of ASD, such as "one night on-call", might alter the autonomic dynamic response to orthostatic challenge and modify the immune response in young physicians., Methods: Fifteen healthy residents in Internal Medicine were studied before and after one night on-call at Rest and during a gravitational stimulus (head up-tilt test, HUT). Heart rate variability (HRV), blood pressure variability (BPV) and baroreflex sensitivity (BRS) were analyzed during Rest and HUT before and after ASD. Plasmatic hormones (epinephrine, norepinephrine, cortisol, renin, aldosterone, ACTH) and tissue inflammatory cytokines were measured at baseline and after ASD., Result: HRV analysis revealed a predominant sympathetic modulation and a parasympathetic withdrawal after ASD. During HUT, the sympathovagal balance shifted towards a sympathetic predominance before and after ASD. However, the magnitude of the autonomic response was lower after ASD. BPV and BRS remained unchanged before and after ASD as the hormone levels, while IFN-γ increased after ASD compared to baseline., Conclusion: In summary, one night of sleep deprivation, at least in this real-life model, seems to affect cardiovascular autonomic response and immune modulation, independently by the activation of the hypothalamic-pituitary axis., (Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Adenosine is the first drug of choice in the treatment of supraventricular arrhythmias. While the effects of adenosine on sympathetic nerve activity (SNA) have been investigated, no information is available on the effects on cardiac vagal nerve activity (VNA). We assessed in rats the responses of cardiac VNA, SNA and cardiovascular variables to intravenous bolus administration of adenosine. In 34 urethane-anaesthetized rats, cardiac VNA or cervical preganglionic sympathetic fibres were recorded together with ECG, arterial pressure and ventilation, before and after administration of three doses of adenosine (100, 500 and 1000 μg kg(-1)). The effects of adenosine were also assessed in isolated perfused hearts (n = 5). Adenosine induced marked bradycardia and hypotension, associated with a significant dose-dependent increase in VNA (+204 ± 56%, P < 0.01; +275 ± 120%, P < 0.01; and +372 ± 78%, P < 0.01, for the three doses, respectively; n = 7). Muscarinic blockade by atropine (5 mg kg(-1), i.v.) significantly blunted the adenosine-induced bradycardia (-56.0 ± 4.5%, P < 0.05; -86.2 ± 10.5%, P < 0.01; and -34.3 ± 9.7%, P < 0.01, respectively). Likewise, adenosine-induced bradycardia was markedly less in isolated heart preparations. Previous barodenervation did not modify the effects of adenosine on VNA. On the SNA side, adenosine administration was associated with a dose-dependent biphasic response, including overactivation in the first few seconds followed by a later profound SNA reduction. Earliest sympathetic activation was abolished by barodenervation, while subsequent sympathetic withdrawal was affected neither by baro- nor by chemodenervation. This is the first demonstration that acute adenosine is able to activate cardiac VNA, possibly through a central action. This increase in vagal outflow could make an important contribution to the antiarrhythmic action of this substance.

Increasing age is associated with a reduction in overall heart rate variability as well as changes in complexity of physiologic dynamics. The aim of this study was to verify if the alterations in autonomic modulation of heart rate caused by the aging process could be detected by Shannon entropy (SE), conditional entropy (CE) and symbolic analysis (SA). Complexity analysis was carried out in 44 healthy subjects divided into two groups: old (n = 23, 63 ± 3 years) and young group (n = 21, 23 ± 2). It was analyzed SE, CE [complexity index (CI) and normalized CI (NCI)] and SA (0V, 1V, 2LV and 2ULV patterns) during short heart period series (200 cardiac beats) derived from ECG recordings during 15 min of rest in a supine position. The sequences characterized by three heart periods with no significant variations (0V), and that with two significant unlike variations (2ULV) reflect changes in sympathetic and vagal modulation, respectively. The unpaired t test (or Mann-Whitney rank sum test when appropriate) was used in the statistical analysis. In the aging process, the distributions of patterns (SE) remain similar to young subjects. However, the regularity is significantly different; the patterns are more repetitive in the old group (a decrease of CI and NCI). The amounts of pattern types are different: 0V is increased and 2LV and 2ULV are reduced in the old group. These differences indicate marked change of autonomic regulation. The CE and SA are feasible techniques to detect alteration in autonomic control of heart rate in the old group.

We propose a multivariate dynamical adjustment (MDA) modeling approach to assess the strength of baroreflex and cardiopulmonary couplings from spontaneous cardiovascular variabilities. Open loop MDA (OLMDA) and closed loop MDA (CLMDA) models were compared. The coupling strength was assessed during progressive sympathetic activation induced by graded head-up tilt. Both OLMDA and CLMDA models suggested that baroreflex coupling progressively increased with tilt table inclination. Only CLMDA model indicated that cardiopulmonary coupling due to the direct link from respiration to heart period gradually decreased with tilt table angles, while that due to the indirect link mediated by systolic arterial pressure progressively increased., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We test the hypothesis that the degree of correlation between ventricular repolarization duration (VRD) and heart period (HP) carries information on cardiac autonomic regulation. The degree of correlation was assessed in the frequency domain using squared coherence function during an experimental protocol known to gradually induce a shift of sympathovagal balance toward sympathetic predominance (ie, graded head-up tilt). We observed a progressive decrease of squared coherence with tilt table inclination, thus confirming the working hypothesis. The VRD-HP uncoupling occurs in the high-frequency band, centered on the respiratory rate, thus suggesting that vagal withdrawal is responsible for the VRD-HP uncoupling., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: Sleep is a complex phenomenon characterized by important modifications throughout life and by changes of autonomic cardiovascular control. Aging is associated with a reduction of the overall heart rate variability (HRV) and a decrease of complexity of autonomic cardiac regulation. The aim of our study was to evaluate the HRV complexity using two entropy-derived measures, Shannon Entropy (SE) and Corrected Conditional Entropy (CCE), during sleep in young and older subjects., Methods: A polysomnographic study was performed in 12 healthy young (21.1±0.8 years) and 12 healthy older subjects (64.9±1.9 years). After the sleep scoring, heart period time series were divided into wake (W), Stage 1-2 (S1-2), Stage 3-4 (S3-4) and REM. Two complexity indexes were assessed: SE(3) measuring the complexity of a distribution of 3-beat patterns (SE(3) is higher when all the patterns are identically distributed and it is lower when some patterns are more likely) and CCE(min) measuring the minimum amount of information that cannot be derived from the knowledge of previous values., Results: Across the different sleep stages, young subjects had similar RR interval, total variance, SE(3) and CCE(min). In the older group, SE(3) and CCE(min) were reduced during REM sleep compared to S1-2, S3-4 and W. Compared to young subjects, during W and sleep the older subjects showed a lower RR interval and reduced total variance as well as a significant reduction of SE(3) and CCE(min). This decrease of entropy measures was more evident during REM sleep., Conclusion: Our study indicates that aging is characterized by a reduction of entropy indices of cardiovascular variability during wake/sleep cycle, more evident during REM sleep. We conclude that during aging REM sleep is associated with a simplification of cardiac control mechanisms that could lead to an impaired ability of the cardiovascular system to react to cardiovascular adverse events.

In physiological conditions, heart period (HP) affects systolic arterial pressure (SAP) through diastolic runoff and Starling's law, but, the reverse relation also holds as a result of the continuous action of baroreflex control. The prevailing mechanism sets the dominant temporal direction in the HP-SAP interactions (i.e., causality). We exploited cross-conditional entropy to assess HP-SAP causality. A traditional approach based on phases was applied for comparison. The ability of the approach to detect the lack of causal link from SAP to HP was assessed on 8 short-term (STHT) and 11 long-term heart transplant (LTHT) recipients (i.e., less than and more than 2 yr after transplantation, respectively). In addition, spontaneous HP and SAP variabilities were extracted from 17 healthy humans (ages 21-36 yr, median age 29 yr; 9 females) at rest and during graded head-up tilt. The tilt table inclinations ranged from 15 to 75° and were changed in steps of 15°. All subjects underwent recordings at every step in random order. The approach detected the lack of causal relation from SAP to HP in STHT recipients and the gradual restoration of the causal link from SAP to HP with time after transplantation in the LTHT recipients. The head-up tilt protocol induced the progressive shift from the prevalent causal direction from HP to SAP to the reverse causality (i.e., from SAP to HP) with tilt table inclination in healthy subjects. Transformation of phases into time shifts and comparison with baroreflex latency supported this conclusion. The proposed approach is highly efficient because it does not require the knowledge of baroreflex latency. The dependence of causality on tilt table inclination suggests that "spontaneous" baroreflex sensitivity estimated using noncausal methods (e.g., spectral and cross-spectral approaches) is more reliable at the highest tilt table inclinations.

We checked whether the observed shift of the dominant causality from heart period (HP) to systolic arterial pressure (SAP) in supine position to the reverse causal direction in upright position could be the result of the exogenous action of respiration on both variables. A model-based approach exploiting a multivariate dynamic adjustment class was utilized to decompose HP and SAP dynamics into partial processes and cancel respiratory-related influences from HP and SAP series. Causality was assessed in the information domain through a bivariate approach based on cross-conditional entropy. After canceling respiratory-related influences we observed the same trend on causality from supine to upright position as detected from the original series, thus suggesting that respiratory influences are not responsible per se for HP-SAP causal relations.

Open-loop linear parametric models were exploited to describe ventricular repolarization duration (VRD) variability during graded head-up tilt. Surface ECG and thoracic movements were recorded in 15 healthy humans (age: 24-54 yr, median: 28 yr; 6 women and 9 men). Tilt table inclinations ranged from 15 to 90 degrees and were varied in steps of 15 degrees . All subjects underwent recordings at every step in random order. Heart period was assessed as the time difference between two consecutive R-wave peaks (RR) and the respiratory signal (R) as the sampling of the thoracic movement signal at the R-wave peaks. VRD was measured automatically as the temporal difference between the R-wave peak and T-wave apex (RT(a)) or T-wave end (RT(e)). The best model decomposed RT variability as due to RR changes (RR-related RT variability) to direct respiratory-related inputs (R-related RT variability) and to unknown rhythmical sources unrelated to RR changes and R (RR-R-unrelated RT variability). Using this model, RT(e) variability was found to be less predictable than RT(a) variability and composed of a smaller fraction of RR-related RT variability and a larger fraction of RR-R-unrelated RT variability. Predictability progressively decreased with tilt table angles, suggesting increased complexity of RT regulation. RT variance progressively increased with tilt table inclination. This increase was characterized by a gradual rise of the amount of RR-R-unrelated RT variability, whereas the amount of RR-related RT variability remained unchanged. These results suggest that the amount of RT variability, complexity of RT dynamics, and amount of RR-R-unrelated RT variability increase with the magnitude of the sympathetic drive directly related to tilt table inclination. We propose the utilization of the amount of RR-R-unrelated RT variability instead of overall RT variability as an indirect measure of autonomic regulation directed to ventricles.

An information domain approach to the assessment of causality was applied to the beat-to-beat variability of heart period and systolic arterial pressure to test the open loop condition along baroreflex in heart transplant recipients. The closed loop between heart period and systolic arterial pressure was detected as open at the level of the baroreflex if systolic arterial pressure is more easily predictable from heart period than vice versa according to a conditional entropy approach. We found that in short-term heart transplant (STHT) recipients (less than 2 years after transplantation) the closed loop between heart period and systolic arterial pressure was open at the level of baroreflex. Baroreflex appeared to be involved in the heart period regulation in long-term heart transplant (LTHT) recipients (more than 2 years after transplantation). The significant linear correlation of causality index on the number of months after transplantation suggests that baroreflex control recovers after transplantation.

We validated a symbolic approach to assess autonomic modulation from pulse interval (PI) and systolic arterial pressure (SAP) series obtained from an animal model of chronic heart failure (CHF). We studied three groups of rats: controls; CHF animals; CHF animals treated with spironolactone (CHF-SP), reducing sympathetic activity in CHF. Simulations confirmed that symbolic analysis captures modifications of cardiovascular regulation in the case of fast dynamics and negligible variance. While spectral indexes did not reveal any significant difference among groups, symbolic analysis pointed out that sympathetic modulation is reduced in CHF group and restored to basal values in CHF-SP one.

Congestive heart failure (CHF) is associated with neurohumoral activation. Only very few studies have examined the progression of autonomic dysfunction in CHF in humans and scanty data are available in animal models of CHF. This study was performed to assess the changes in cardiac autonomic modulation during the progression of CHF in a rat model, using an innovative analysis of heart rate variability. Progression of cardiovascular autonomic dysfunction was assessed in a rat model of CHF induced by coronary artery ligation. Spectral and symbolic analyses were performed on heart period (approximated with pulse interval, PI) and systolic arterial pressure (SAP) signals, acquired ~2 and ~4 weeks after the surgical procedure. As CHF developed, symbolic analysis revealed a decrease of rhythmical physiological sympathetic modulation, as indicated by the reduction of the percentage of stable patterns. In addition, symbolic analysis revealed that runs of short-long-short and/or long-short-long PI values and high-low-high and/or low-high-low SAP values were more and more frequent as CHF progressed. On the contrary, spectral analysis of PI and SAP series was not able to detect any impairment of autonomic regulation. Indeed, low frequency and high frequency powers derived from both PI and SAP series were not significantly changed. These data indicate that the autonomic cardiovascular modulation is altered during the progression of CHF and that symbolic analysis seems to be more suitable than spectral analysis to describe alterations of heart period dynamics and of cardiovascular regulation in this animal model of CHF.

Anesthesia during asleep-awake craniotomy should provide adequate analgesia and sedation whereas permitting language testing. In this work, we used the analysis of heart rate variability (HRV) to quantify the sympatho-vagal balance and better evaluate patient's stress response during asleep-awake craniotomy. Patients admitted to our hospital for tumor resection with language testing were studied (n=21, age range: 22 to 53 y ). Heart rate and systolic arterial blood pressure were collected at 5 time points: T1: preanesthesia; T2: dura mater opening; T3: cortical mapping; T4: subcortical mapping; T5: dura mater suturing. Patients were anesthetized with propofol/remifentanil infusion and ventilated via laryngeal mask during T2, but were awakened for language testing at T3 and T4, and resedated with remifentanil during T5. At each time point, HRV was analyzed by power spectrum analysis: overall variance, very low frequency (VLF), low frequency (LF) and high frequency (HF) powers, and LF/HF ratio (an index of prevalence of sympathetic over parasympathetic tone) were derived. A significant increase in both heart rate and systolic arterial blood pressure was observed from time point T3 through T5 (P<0.05, compared with T1). HRV analysis revealed that the LF/HF ratio progressively increased to reach values during T4 that were significantly higher than preanesthesia values (P<0.05). During T5, LF/HF ratio returned to preanesthesia level. HRV analysis confirmed the presence of moderate intraoperative stress response, indicating a significant increase in the LF/HF ratio during the awake phases. This information might help in tailoring the protocol and the duration of awake phase according to the individual autonomic response.

The neural regulation of circulatory function is mainly effected through the interplay of the sympathetic and vagal outflows. This interaction can be explored by assessing cardiovascular rhythmicity with appropriate spectral methodologies. Spectral analysis of cardiovascular signal variability, and in particular of RR period (heart rate variability, HRV), is a widely used procedure to investigate autonomic cardiovascular control and/or target function impairment. The oscillatory pattern which characterizes the spectral profile of heart rate and arterial pressure short-term variability consists of two major components, at low (LF, 0.04-0.15Hz) and high (HF, synchronous with respiratory rate) frequency, respectively, related to vasomotor and respiratory activity. With this procedure the state of sympathovagal balance modulating sinus node pacemaker activity can be quantified in a variety of physiological and pathophysiological conditions. Changes in sympathovagal balance can be often detected in basal conditions, however a reduced responsiveness to an excitatory stimulus is the most common feature that characterizes numerous pathophysiological states. Moreover the attenuation of an oscillatory pattern or its impaired responsiveness to a given stimulus can also reflect an altered target function and thus can furnish interesting prognostic markers. The dynamic assessment of these autonomic changes may provide crucial diagnostic, therapeutic and prognostic information, not only in relation to cardiovascular, but also non-cardiovascular disease. As linear methodologies fail to provide significant information in conditions of extremely reduced variability (e.g. strenuous exercise, heart failure) and in presence of rapid and transients changes or coactivation of the two branches of autonomic nervous system, the development of new non-linear approaches seems to provide a new perspective in investigating neural control of cardiovascular system.

Open loop linear parametric modeling approach was applied to describe the variability of the ventricular depolarization and repolarization duration (i.e. the QT interval from the ECG). Several model structures were compared. The model maximizing the goodness of fit describes the QT interval as a linear combination of its own past values plus two exogenous influences (i.e. heart period interval and respiration) and a colored noise. When this model was applied to a protocol imposing a progressive increase of the sympathetic activity and modulation (i.e. the graded head-up tilt), the goodness of fit gradually decreased, thus suggesting a progressive uncoupling between QT duration and heart period that cannot be the result of influences unrelated to heart period changes.

Hyperthyroidism is a pathological condition characterized by an altered autonomic cardiovascular control, resulting in an increase of the sympathetic and a decrease of the parasympathetic modulation of heart rate variability. Recently, the entropy-based indices derived from short-term heart period variability have been proved to be helpful in evaluating the autonomic cardiovascular modulation. The aim of our study was to evaluate the autonomic cardiovascular modulation of hyperthyroid subjects at rest and during standing using spectral parameters and corrected conditional entropy indices derived from short-term heart period variability in 12 hyperthyroid (HYPTH) and 9 normal healthy (N) females. Mean heart period was significantly decreased by standing both in N and HYPTH and the LF power expressed in normalized units was increased. The respiratory rate was faster in the HYPTH group compared to N and complexity was significantly greater in HYPTH compared to N during standing. Results suggested an enhanced complexity of cardiovascular control in HYPTH, more evident in a condition of sympathetic activation. The increased complexity of the cardiovascular regulation is probably not completely due to autonomic control but also to other influences, such as metabolic effects of thyroid hormones impinging upon respiratory control mechanisms and, therefore, on cardiorespiratory coupling.

Complexity (or its opposite, regularity) of heart period variability has been related to age and disease but never linked to a progressive shift of the sympathovagal balance. We compare several well established estimates of complexity of heart period variability based on entropy rates [i.e., approximate entropy (ApEn), sample entropy (SampEn), and correct conditional entropy (CCE)] during an experimental protocol known to produce a gradual shift of the sympathovagal balance toward sympathetic activation and vagal withdrawal (i.e., the graded head-up tilt test). Complexity analysis was carried out in 17 healthy subjects over short heart period variability series ( approximately 250 cardiac beats) derived from ECG recordings during head-up tilt with table inclination randomly chosen inside the set {0, 15, 30, 45, 60, 75, 90}. We found that 1) ApEn does not change significantly during the protocol; 2) all indices measuring complexity based on entropy rates, including ad hoc corrections of the bias arising from their evaluation over short data sequences (i.e., corrected ApEn, SampEn, CCE), evidence a progressive decrease of complexity as a function of the tilt table inclination, thus indicating that complexity is under control of the autonomic nervous system; 3) corrected ApEn, SampEn, and CCE provide global indices that can be helpful to monitor sympathovagal balance.

Two symbolic indexes, the percentage of sequences characterized by three heart periods with no significant variations (0V%) and that with two significant unlike variations (2UV%), have been found to reflect changes in sympathetic and vagal modulations, respectively. We tested the hypothesis that symbolic indexes may track the gradual shift of the cardiac autonomic modulation during an incremental head-up tilt test. Symbolic analysis was carried out over heart period variability series (250 cardiac beats) derived from ECG recordings during a graded head-up tilt test (0, 15, 30, 45, 60, 75, and 90 degrees ) in 17 healthy subjects. The percentage of subjects showing a significant linear correlation (Spearman rank-order correlation) with tilt angles was utilized to evaluate the performance of symbolic analysis. Spectral analysis was carried out for comparison over the same series. 0V% progressively increased with tilt angles, whereas 2UV% gradually decreased. The decline of 2UV% was greater than the increase of 0V% at low tilt angles. Linear correlation with tilt angles was exhibited in a greater percentage of subjects for 0V% and 2UV% than for any spectral index. Our findings suggest that symbolic analysis performed better than spectral analysis and, thus, is a suitable methodology for assessment of the subtle changes of cardiac autonomic modulation induced by a graded head-up tilt test. Moreover, symbolic analysis indicates that the changes of cardiac sympathetic and vagal modulations observed during this protocol were reciprocal but characterized by different absolute magnitudes.

A cross-conditional entropy approach was applied to evaluate the degree of coupling between the beat-to-beat series of heart period (RR interval) and ventricular repolarization duration (QT interval). The strength of the QT-RR coupling was measured during graded head-up tilt test with table inclination randomly chosen in the set {0,15,30,45,60,75,90} in 17 healthy subjects. We found that RR and QT variabilities are significantly coupled during the entire experimental protocol and the strength of the QT-RR variability interactions progressively decreases as a function of the tilt angles. Results suggest that the fraction of QT interval variability independent of RR interval changes is not constant but depends on the level of sympathetic activity and/or amplitude of sympathetic modulation.