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The present study explores the modifications of cardiovascular autonomic control (CAC) during wake and sleep time and the systemic inflammatory profile associated with exposure to indoor air pollution (IAP) in a cohort of healthy subjects. Twenty healthy volunteers were enrolled. Indoor levels of fine particulate matter (PM 2.5 ), nitrogen dioxide (NO 2 ) and volatile organic compounds (VOCs) were monitored using a portable detector for 7 days. Together, a 7-day monitoring was performed through a wireless patch that continuously recorded electrocardiogram, respiratory activity and actigraphy. Indexes of CAC during wake and sleep time were derived from the biosignals: heart rate and low-frequency to high-frequency ratio (LF/HF), index of sympathovagal balance with higher values corresponding to a predominance of the sympathetic branch. Cyclic variation of heart rate index (CVHRI events/hour) during sleep, a proxy for the evaluation of sleep apnea, was assessed for each night. After the monitoring, blood samples were collected to assess the inflammatory profile. Regression and correlation analyses were performed. A positive association between VOC exposure and the CVHRI (Δ% = +0.2% for 1 μg/m 3 VOCs, p = 0.008) was found. The CVHRI was also positively associated with LF/HF during sleep, thus higher CVHRI values corresponded to a shift of the sympathovagal balance towards a sympathetic predominance (r = 0.52; p = 0.018). NO 2 exposure was positively associated with both the pro-inflammatory biomarker TREM-1 and the anti-inflammatory biomarker IL-10 (Δ% = +1.2% and Δ% = +2.4%, for 1 μg/m 3 NO 2 ; p = 0.005 and p = 0.022, respectively). The study highlights a possible causal relationship between IAP exposure and higher risk of sleep apnea events, associated with impaired CAC during sleep, and a pro-inflammatory state counterbalanced by an increased anti-inflammatory response in healthy subjects. This process may be disrupted in vulnerable populations, leading to a harmful chronic pro-inflammatory profile. Thus, IAP may emerge as a critical and often neglected risk factor for the public health that can be addressed through targeted preventive interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective. To determine the optimal frequency and site of stimulation for transcutaneous vagus nerve stimulation (tVNS) to induce acute changes in the autonomic profile (heart rate (HR), heart rate variability (HRV)) in healthy subjects (HS) and patients with heart failure (HF). Approach. We designed three single-blind, randomized, cross-over studies: (1) to compare the acute effect of left tVNS at 25 Hz and 10 Hz ( n = 29, age 60 ± 7 years), (2) to compare the acute effect of left and right tVNS at the best frequency identified in study 1 ( n = 28 age 61 ± 7 years), and (3) to compare the acute effect of the identified optimal stimulation protocol with sham stimulation in HS and HF patients ( n = 30, age 59 ± 5 years, and n = 32, age 63 ± 7 years, respectively). Main results. In study 1, left tragus stimulation at 25 Hz was more effective than stimulation at 10 Hz in decreasing HR (-1.0 ± 1.2 bpm, p < 0.001 and -0.5 ± 1.6 bpm, respectively) and inducing vagal effects (significant increase in RMSSD, and HF power). In study 2, the HR reduction was greater with left than right tragus stimulation (-0.9 ± 1.5 bpm, p < 0.01 and -0.3 ± 1.4 bpm, respectively). In study 3 in HS, left tVNS at 25 Hz significantly reduced HR, whereas sham stimulation did not (-1.1 ± 1.2 bpm, p < 0.01 and -0.2 ± 2.9 bpm, respectively). In HF patients, both active and sham stimulation produced negligible effects. Significance. Left tVNS at 25 Hz is effective in acute modulation of cardiovascular autonomic control (HR, HRV) in HS but not in HF patients (NCT05789147)., (© 2024 Institute of Physics and Engineering in Medicine.)

Background: Rett syndrome (RTT) is a rare neurological disorder primarily associated with mutations in the methyl-CpG-binding protein 2 (MECP2) gene. The syndrome is characterized by cognitive, social, and physical impairments, as well as sleep disorders and epilepsy. Notably, dysfunction of the autonomic nervous system is a key feature of the syndrome. Although Heart Rate Variability (HRV) has been used to investigate autonomic nervous system dysfunction in RTT during wakefulness, there is still a significant lack of information regarding the same during sleep. Therefore, our aim was to investigate cardiovascular autonomic modulation during sleep in subjects with RTT compared to an age-matched healthy control group (HC)., Method: A complete overnight polysomnographic (PSG) recording was obtained from 11 patients with Rett syndrome (all females, 10 ± 4 years old) and 11 HC (all females, 11 ± 4 years old; p = 0.48). Electrocardiogram and breathing data were extracted from PSG and divided into wake, non-REM, and REM sleep stages. Cardiac autonomic control was assessed using symbolic non-linear heart rate variability analysis. The symbolic analysis identified three patterns: 0 V% (sympathetic), 2UV%, and 2LV% (vagal)., Results: The 0 V% was higher in the RTT group than in the HC group during wake, non-REM, and REM stages (p < 0.01), while the 2LV and 2UV% were lower during wake and sleep stages (p < 0.01). However, the 0 V% increased similarly from the wake to the REM stage in both RTT and HC groups., Conclusions: Therefore, the sympatho-vagal balance shifted towards sympathetic predominance and vagal withdrawal during wake and sleep in RTT, although cardiac autonomic dynamics were preserved during sleep., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Malnutrition results in autonomic imbalance and heart hypertrophy. Overexpression of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in the left ventricles (LV) is linked to hypertrophied hearts and abnormal myocardium automaticity. Given that ivabradine (IVA) has emerging pleiotropic effects, in addition to the widely known bradycardic response, this study evaluated if IVA treatment could repair the autonomic control and cardiac damages in malnourished rats., Aim: Assess the impact of IVA on tonic cardiovascular autonomic control and its relationship with hemodynamics regulation, LV inflammation, and HCN gene expression in post-weaning protein malnutrition condition., Main Methods: After weaning, male rats were divided into control (CG; 22 % protein) and malnourished (MG; 6 % protein) groups. At 35 days, groups were subdivided into CG-PBS, CG-IVA, MG-PBS and MG-IVA (PBS 1 ml/kg or IVA 1 mg/kg) received during 8 days. We performed jugular vein cannulation and electrode implant for drug delivery and ECG registration to assess tonic cardiovascular autonomic control; femoral cannulation for blood pressure (BP) and heart rate (HR) assessment; and LV collection to evaluate ventricular remodeling and HCN gene expression investigation., Key Findings: Malnutrition induced BP and HR increases, sympathetic system dominance, and LV remodeling without affecting HCN gene expression. IVA reversed the cardiovascular autonomic imbalance; prevented hypertension and tachycardia; and inhibited the LV inflammatory process and fiber thickening caused by malnutrition., Significance: Our findings suggest that ivabradine protects against malnutrition-mediated cardiovascular damage. Moreover, our results propose these effects were not attributed to HCN expression changes, but rather to IVA pleiotropic effects on autonomic control and inflammation., Competing Interests: Declaration of competing interest Authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Although cardiac autonomic modulation has been studied in several respiratory diseases, the evidence is limited on lung transplantation, particularly on its acute and chronic effects. Thus, we aimed to evaluate cardiac autonomic modulation before and after bilateral lung transplantation (BLT) through a prospective study on patients enrolled while awaiting transplant., Methods: Twenty-two patients on the waiting list for lung transplantation (11 women, age 33 [24-51] years) were enrolled in a prospective study at Ospedale Maggiore Policlinico Hospital in Milan, Italy. To evaluate cardiac autonomic modulation, ten minutes ECG and respiration were recorded at different time points before (T0) and 15 days (T1) and 6 months (T2) after bilateral lung transplantation. As to the analysis of cardiac autonomic modulation, heart rate variability (HRV) was assessed using spectral and symbolic analysis. Entropy-derived measures were used to evaluate complexity of cardiac autonomic modulation. Comparisons of autonomic indices at different time points were performed., Results: BLT reduced HRV total power, HRV complexity and vagal modulation, while it increased sympathetic modulation in the acute phase (T1) compared to baseline (T0). The HRV alterations remained stable after 6 months (T2)., Conclusion: BLT reduced global variability and complexity of cardiac autonomic modulation in acute phases, and these alterations remain stable after 6 months from surgery. After BLT, a sympathetic predominance and a vagal withdrawal could be a characteristic autonomic pattern in this population.

Objective: To compare autonomic heart rate variability (HRV) parameters at rest and during active stand in a population of SSc patients, taking into account SSc subsets age-matched to healthy control subjects., Methods: Sixty-nine consecutive SSc patients were enrolled in study; these included 12 subjects with early SSc, 39 with limited cutaneous (lcSSc) and 18 with diffuse cutaneous SSc (dcSSc) along with 36 age- and sex-matched healthy controls (HC). ECG and respiration were recorded in supine position and in orthostatism (ORT). HRV analysis was performed on samples of 300 beats. Spectral analysis identified two oscillatory components, low frequency (LFnu, sympathetic) and high frequency (HFnu, vagal). Symbolic analysis identified three patterns, 0 V%, (sympathetic) and 2UV% and 2LV%, (vagal). The %∆ORT was calculated from the differences between HRV in ORT and SUP, normalized (%) by the HRV values at rest., Results: SSc as a whole had higher markers of sympathetic (LF, 0 V%) and lower markers of vagal modulation (HR, 2UV%, 2LV%) compared to HCs. In addition, %∆LFnu, %∆HFnu, %∆0 V, %∆2UV and %∆2LV were lower in SSc than HC. dcSSc and lcSSc were dissimilar to HC as far as rest indexes were concerned (↑LF/HF, ↑LFnu, ↓HFnu, ↑0 V% and ↓2UV%) while no differences could be detected between HC and EaSSc., Conclusion: SSc showed a reduced vagal and increased sympathetic modulation at rest and a blunted autonomic response to ORT in comparison to HC. These alterations were mostly detectable in the advanced and fibrotic forms of SSc (dcSSc and lcSSc), while EaSSc were similar to HC., (Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Objective: Symbolic transformations of the cardiac interbeat interval series yield a coarse-grained description of the dynamical information of the underlying system and complement standard measures of heart rate variability. The most commonly utilized coarse graining procedures are strongly influenced by the presence of a few extreme values wasting precious symbols to code very unlikely values., Approach: Here, we used a transformation procedure that ensured the appearance of each symbol with equal probability using a short alphabet, A 4   =  {0, 1, 2, 3}, and a long alphabet, A 6   =  {0, 1, 2, 3, 4, 5}. The procedure was applied to the cardiac interbeat interval series of 17 healthy subjects, obtained during graded head-up tilt tests at tilt table inclinations of 0°, 15°, 30°, 45°, 60°, 75°, 90°. The dynamics of the symbolic series was assessed by the rate of symbolic pattern categories. Symbolic patterns of length three were grouped according to the variations of the symbols in each pattern: no variation (0V%), one variation (1V%), two like variations (2LV%) and two unlike variations (2UV%) of the symbols., Main Results: As for the alphabet A 4 , the linear regression analysis on tilt angle showed that 0V% increased with increasing tilt angle whereas 1V%, 2LV% and 2UV% decreased. As for the alphabet A 6 , the categories 0V%, and 1V% increased with increasing tilt angle whereas 2LV% and 2UV% decreased., Significance: The symbolic transformation ensuring a uniform distribution of the symbols is capable of reflecting changes in the cardiac autonomic nervous system during graded head-up tilt. This approach is more robust against outliers and data with skewed distributions compared to previously used symbolizations.

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.)

Background: Blood pressure (BP) variability can be evaluated by 24-hour ambulatory BP monitoring (24h-ABPM), but its concordance with results from finger BP measurement (FBPM) has not been established yet., Objective: The aim of this study was to compare parameters of short-term (24h-ABPM) with very short-term BP variability (FBPM) in healthy (C) and diabetic-hypertensive (DH) subjects., Methods: Cross-sectional study with 51 DH subjects and 12 C subjects who underwent 24h-ABPM [extracting time-rate, standard deviation (SD), coefficient of variation (CV)] and short-term beat-to-beat recording at rest and after standing-up maneuvers [FBPM, extracting BP and heart rate (HR) variability parameters in the frequency domain, autoregressive spectral analysis]. Spearman correlation coefficient was used to correlate BP and HR variability parameters obtained from both FBPM and 24h-ABPM (divided into daytime, nighttime, and total). Statistical significance was set at p < 0.05., Results: There was a circadian variation of BP levels in C and DH groups; systolic BP and time-rate were higher in DH subjects in all periods evaluated. In C subjects, high positive correlations were shown between time-rate index (24h-ABPM) and LF component of short-term variability (FBPM, total, R = 0.591, p = 0.043); standard deviation (24h-ABPM) with LF component BPV (FBPM, total, R = 0.608, p = 0.036), coefficient of variation (24h-ABPM) with total BPV (FBPM, daytime, -0.585, p = 0.046) and alpha index (FBPM, daytime, -0.592, p = 0.043), time rate (24h-ABPM) and delta LF/HF (FBPM, total, R = 0.636, p = 0.026; daytime R = 0,857, p < 0.001). Records obtained from DH showed weak positive correlations., Conclusions: Indices obtained from 24h-ABPM (total, daytime) reflect BP and HR variability evaluated by FBPM in healthy individuals. This does not apply for DH subjects.

Aims: Bradycardic agents are currently used in the treatment of angina and heart failure; direct information on their effects on cardiac sympathetic nerve activity (SNA) may be relevant to their chronic use. The present study evaluates the effect of pacemaker inhibition on SNA; direct nerve recordings and indirect autonomic indexes are compared., Methods and Results: Experiments were performed in 18 anaesthetized rats. SNA (direct nerve recording) and heart rate variability (HRV) indexes were evaluated in parallel. All parameters were recorded 10 min before to 60 min after administration of the If blocker ivabradine (IVA; 2 mg/kg, i.v.; n = 8) or vehicle (VEH; n = 5). IVA-induced RR interval (RR) prolongation (at 60 min +15.0 ± 7.1%, P < 0.01) was associated with decreased diastolic arterial pressure (DAP; -17.3 ± 8.4%, P < 0.05) and increased SNA (+51.1 ± 12.3%, P < 0.05). These effects were accompanied by increased RR variance (RRσ(2)), which showed strong positive correlation with RR. Frequency-domain HRV indexes (in normalized units) were unchanged by IVA. After baroreceptor reflexes had been eliminated by sino-aortic denervation (n = 5), similar IVA-induced RR prolongation (at 60 min +14.3 ± 5.9%, NS vs. intact) was associated with a larger DAP reduction (-30.9 ± 4.1%, P < 0.05 vs. intact), but failed to affect SNA., Conclusions: (i) IVA-induced bradycardia was associated with increased SNA, resulting from baroreceptor unloading; if this applied to chronic IVA use in humans, it would be of relevance for therapeutic use of the drug. (ii) Whenever mean HR is concomitantly changed, time-domain HRV indexes should not be unequivocally interpreted in terms of autonomic balance., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

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.)

Traditional measures of heart rate variability (HRV) in the time or frequency domain (e.g. standard deviation of normal-to-normal intervals, SDNN, or the high frequency component of spectral analysis, HF) may be used to track vagal and sympathetic modulation directed to the sinus node. In this study, we assess the ability of symbolic analysis to monitor cardiac autonomic regulation during two autonomic challenges (phenylephrine and nitroprusside; low and high dose of atropine). To assess the effect of the coarse graining procedure, symbolic series obtained from four different transformations over the original series and the series of successive differences of the original values. The analysis focused on patterns of length 3 and exploited a redundancy reduction strategy to group patterns into a small number of families. It turns out that each symbolic series created by the four transformations still contained sufficient dynamical features to quantify differences of cardiovascular changes during the pharmacological challenges. The symbolic series created by transformations of the beat-to-beat interview, i.e RR interval series, showed that patterns without variations (0V) appear more often during a high dose of atropine compared to rest or to a low dose of atropine. Furthermore, patterns with two unlike variations (2UV) appear more often during a low dose of atropine and less often during a high dose of atropine. Differences of nitroprusside and phenylephrine could also be assessed by patterns with these variations. In conclusion, the changes of cardiovascular regulation during pharmacological challenges can be assessed by the analysis of symbolic dynamics derived from the RR interval series independently of the specific symbolic transformation.

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.)

Coarse graining of physiological time series such as the cardiac interbeat interval series by means of a symbolic transformation retains information about dynamical properties of the underlying system and complements standard measures of heart rate variability. The transformations of the original time series to the coarse grained symbolic series usually lead to a non-uniform occurrence of the different symbols, i.e. some symbols appear more often than others influencing the results of the subsequent symbolic series analysis. Here, we defined a transformation procedure to assure that each symbol appears with equal probability using a short alphabet {0,1,2,3} and a long alphabet {0,1,2,3,4,5}. The procedure was applied to the cardiac interbeat interval series RRi of 17 healthy subjects obtained during graded head-up tilt testing. The symbolic dynamics is analyzed by means of the occurrence of short sequences (`words') of length 3. The occurrence of words is grouped according to words without variations of the symbols (0V%), one variation (1V%), two like variations (2LV%) and two unlike variations (2UV%). Linear regression analysis with respect to tilt angle showed that for the short alphabet 0V% increased with increasing tilt angle whereas 1V%, 2LV% and 2UV% decreased. For the long alphabet 0V%, and 1V% increased with increasing tilt angle whereas 2LV% and 2UV% decreased. These results were slightly better compared to the results from non-uniform symbolic transformations reflecting the deviation from the mean. In conclusion, the symbolic transformation assuring the appearance of symbols with equal probability is capable of reflecting changes of the cardiac autonomic nervous system during graded head-up tilt. Furthermore, the transformation is independent of the time series' distribution.

Objective: To investigate the effects of hormone replacement therapy (HRT) on heart rate variability (HRV) in healthy postmenopausal women., Methods: Two groups were evaluated: group 1 (G1): 20 women not undergoing HRT (60 ± 5.89 years), group 2 (G2): 20 women undergoing HRT (59 ± 5.70 years). The HRTs involved were either conjugated equine estrogen with or without medroxyprogesterone, synthetic estrogen hormone, estradiol associated with norethisterone acetate or isoflavonoids. Electrocardiogram was recorded in the supine position for 10 min. Spectral analysis included low and high frequencies in absolute (LF and HF) and normalized units (LFnu and HFnu), which are predominantly cardiac sympathetic modulation (CSM) and cardiac vagal modulation (CVM) indicators, respectively. The LF/HF ratio was also calculated. Symbolic analysis involved the following indexes: 0V % (CSM indicator), 1V % (CSM and CVM indicators), 2LV % (predominantly CVM indicator) and 2UV % (CVM indicator). Shannon and conditional entropies were also calculated., Results: Spectral analysis demonstrated that HRT affected HRV. LF, LFnu and LF/HF ratio were higher (showing increased CSM), while HFnu was lower (representing decreased CVM) in G2 than in G1. Correlations between complexity indices and HFnu were significant and positive only in G1., Interpretation: Women undergoing HRT presented higher CSM and lower CVM than those who were not. Moreover, the expected positive relationship between CVM and complexity of HRV was found only in control group, thus indicating that CVM in women under therapy drop below a minimal value necessary to the association to become apparent, suggesting an unfavorable cardiac autonomic modulation in spite of HRT.

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.)

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.)

Personality characteristics, e.g. aggressiveness, have long been associated with an increased risk of cardiac disease. However, the underlying mechanisms remain unclear. In this study we used a rodent model for characterizing cardiac autonomic modulation in rats that differ widely in their level of aggressive behavior. To reach this goal, high-aggressive (HA, n = 10) and non-aggressive (NA, n = 10) rats were selected from a population (n = 121) of adult male Wild-type Groningen rats on the basis of their latency time to attack (ALT, s) a male intruder in a resident-intruder test lasting 600 s. In order to obtain information on their cardiac autonomic modulation, ECG recordings were subsequently obtained via radiotelemetry at rest, during stressful stimuli and under autonomic pharmacological manipulations, and analyzed by means of time- and frequency-domain indexes of heart rate variability. During resting conditions, HA rats (ALT<90 s) displayed reduced heart rate variability, mostly in terms of lower vagal modulation compared to NA rats (ALT>600 s). Exposure to stressful stimuli (i.e. restraint and psychosocial stress) provoked similar tachycardic responses between the two groups. However, under stress conditions HA rats displayed a reduced vagal antagonism and an increased incidence of tachyarrhythmias compared to NA rats. In addition, beta-adrenergic pharmacological stimulation induced a much larger incidence of ventricular tachyarrhythmias in HA rats compared to NA counterparts. These findings are consistent with the view that high levels of aggressive behavior in rats are associated to signs of cardiac autonomic impairment and increased arrhythmogenic susceptibility that may predict vulnerability to cardiac morbidity and mortality.

The analysis of symbolic dynamics applied to physiological time series is able to retrieve information about dynamical properties of the underlying system that cannot be gained with standard methods like e.g. spectral analysis. Different approaches for the transformation of the original time series to the symbolic time series have been proposed. Yet the differences between the approaches are unknown. In this study three different transformation methods are investigated: (1) symbolization according to the deviation from the average time series, (2) symbolization according to several equidistant levels between the minimum and maximum of the time series, (3) binary symbolization of the first derivative of the time series. Each method was applied to the cardiac interbeat interval series RR(i) and its difference ΔRR(I) of 17 healthy subjects obtained during head-up tilt testing. The symbolic dynamics of each method is analyzed by means of the occurrence of short sequences ('words') of length 3. The occurrence of words is grouped according to words without variations of the symbols (0V%), words with one variation (1V%), two like variations (2LV%) and two unlike variations (2UV%). Linear regression analysis showed that for method 1 0V%, 1V%, 2LV% and 2UV% changed with increasing tilt angle. For method 2 0V%, 2LV% and 2UV% changed with increasing tilt angle and method 3 showed changes for 0V% and 1V%. In conclusion, all methods are capable of reflecting changes of the cardiac autonomic nervous system during head-up tilt. All methods show that even the analysis of very short symbolic sequences is capable of tracking changes of the cardiac autonomic regulation during head-up tilt testing.

It is unclear whether the complexity of the variability of the systolic arterial pressure (SAP) provides complementary information to that of the heart period (HP). The complexity of HP and SAP variabilities was assessed from short beat-to-beat recordings (i.e., 256 cardiac beats). The evaluation was made during a pharmacological protocol that induced vagal blockade with atropine or a sympathetic blockade (beta-adrenergic blockade with propranolol or central sympathetic blockade with clonidine) alone or in combination, during a graded head-up tilt, and in patients with Parkinson's disease (PD) without orthostatic hypotension undergoing orthostatic challenge. Complexity was quantified according to the mean square prediction error (MSPE) derived from univariate autoregressive (AR) and multivariate AR (MAR) models. We found that: 1) MSPE(MAR) did not provide additional information to that of MSPE(AR); 2) SAP variability was less complex than that of HP; 3) because HP complexity was reduced by either vagal blockade or vagal withdrawal induced by head-up tilt and was unaffected by beta-adrenergic blockade, HP was under vagal control; 4) because SAP complexity was increased by central sympathetic blockade and was unmodified by either vagal blockade or vagal withdrawal induced by head-up tilt, SAP was under sympathetic control; 5) SAP complexity was increased in patients with PD; and 6) during orthostatic challenge, the complexity of both HP and SAP variabilities in patients with PD remained high, thus indicating both vagal and sympathetic impairments. Complexity indexes derived from short HP and SAP beat-to-beat series provide complementary information and are helpful in detecting early autonomic dysfunction in patients with PD well before circulatory symptoms become noticeable.

Objective: Coronary artery disease (CAD) and acute myocardial infarction (AMI) are associated with a reduction of heart rate variability (HRV). The aim of this study was to compare the HRV of CAD patients with and without AMI (CAD-AMI) with health-matched controls by linear (spectral analysis) and nonlinear [Shannon entropy (SE), conditional entropy (CE) and symbolic analysis (SA)] analysis., Methods: Fifty-eight men were divided into three groups: healthy (n = 19, 57 ± 4 years), CAD (n = 20, 56 ± 10 years) and CAD-AMI (n = 19, 54 ± 12 years). The RR intervals were recorded at rest in the supine position for 10 min with an HR monitor (Polar(®)S810i). A series of 250 beats was selected to analyze variance, spectral analysis, SE, CE [complexity index (CI), normalized CI (NCI)] and SA (0V, 1V, 2LV and 2ULV patterns), as well as 0V (no significant variation) and 2ULV (two significant unlike variations), which reflect sympathetic and vagal modulation, respectively. One-way ANOVA (or the Kruskal-Wallis test when appropriate) and Pearson correlation were used., Results: The CAD group had higher body mass index and weight than the CAD-AMI group, but no differences were found between the healthy and AMI groups. There were no differences between the groups regarding linear and nonlinear analysis. The 0V and 2ULV patterns were significantly correlated with the SE, CI and NCI of the three groups., Interpretation: There was no difference between the groups regarding cardiac autonomic modulation by linear and nonlinear methods, which may be due to beta-blocker use, coronary angioplasty and the exercise capacity of healthy subjects.

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.

Symbolic dynamics derived from heart rate variability (HRV) is able to reflect changes of cardiac autonomic modulations on short time scales in spite of the considerable reduction of information involved. However, the link between the appearance of specific symbolic patterns and the activity of the autonomic nervous system has not yet been elucidated. In this study, we investigate the symbolic dynamics that reflect acceleration (='1') and deceleration (='0') of the instantaneous heart rate. The resulting binary series is analyzed with respect to the regularity of binary patterns of length 8 using Approximate Entropy (ApEn). Binary patterns were grouped according to the level of their regularity as assessed by ApEn. ECG recordings were obtained from 17 healthy subjects during graded head-up tilt (0, 15, 30, 45, 60, 75, and 90°). The linear correlation (Spearman correlation coefficient) between tilt angle and the occurrence of binary patterns was evaluated. The results show that regular binary patterns occurred more often with increasing tilt angle whereas the occurrence of some irregular patterns decreased. Some binary patterns did not show a change of occurrence during tilt. When compared to the results of spectral analysis, regular binary patterns reflect sympathetic modulations whereas irregular binary patterns reflect parasympathetic modulations. The parameters derived from binary symbolic dynamics reflect changes of autonomic modulations during graded head-up tilt and are not fully correlated to the spectral markers of HRV., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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.

Purpose: Heart rate variability (HRV) decreases after an acute myocardial infarction (AMI) due to changes in cardiac autonomic balance. The purpose of the present study, therefore, was to evaluate the effects of a progressive exercise protocol used in phase I cardiac rehabilitation on the HRV of patients with post-AMI., Material and Methods: Thirty-seven patients who had been admitted to hospital with their first non-complicated AMI were studied. The treated group (TG, n=21, age=52±12 years) performed a 5-day programme of progressive exercise during phase I cardiac rehabilitation, while the control group (CG, n=16, age=54±11 years) performed only respiratory exercises. Instantaneous heart rate (HR) and RR interval were acquired by a HR monitor (Polar®S810i). HRV was analysed by frequency domain methods. Power spectral density was expressed as normalised units (nu) at low (LF) and high (HF) frequencies, and as LF/HF., Results: After 5 days of progressive exercise, the TG showed an increase in HFnu (35.9±19.5 to 65.19±25.4) and a decrease in LFnu and LF/HF (58.9±21.4 to 32.5±24.1; 3.12±4.0 to 1.0±1.5, respectively) in the resting position (p<0.05). No changes were observed in the CG., Conclusions: A progressive physiotherapeutic exercise programme carried out during phase I cardiac rehabilitation, as supplement to clinical treatment increased vagal and decreased sympathetic cardiac modulation in patients with post-AMI., (© 2011 Informa UK, Ltd.)

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.

The objective of this study was to use linear and non-linear methods to investigate cardiac autonomic modulation in healthy elderly men and women in response to a postural change from the supine to the standing position. Fourteen men (66.1 ± 3.5 years) and 10 women (65.3 ± 3.3 years) were evaluated. Beat-to-beat heart rate was recorded in the supine and standing positions. Heart rate variability was studied by spectral analysis, including both low (LFnu-cardiac sympathetic modulation (CSM) indicator) and high (HFnu-cardiac vagal modulation (CVM) indicator) frequencies in normalized units as well as the low frequency/high frequency (LF/HF) ratio. Symbolic analysis was performed using the following indexes: 0V% (CSM indicator), 1V% (CSM and CVM indicators), 2LV% (predominantly CVM indicator) and 2ULV% (CVM indicator). Shannon entropy was also calculated. Men presented higher LFnu and LF/HF ratio and lower HFnu and 1V% symbolic index (57.56, 4.14, 40.53, 45.96, respectively) than women (24.60, 0.45, 72.47, 52.69, respectively) in the supine position. Shannon entropy was higher among men (3.53) than among women (3.33) in the standing position, and also increased according to postural change in men (3.25; 3.53). During postural change, the LFnu (24.60; 49.85) and LF/HF ratio (0.45; 1.72) increased, with a concomitant decrease in HFnu (72.47; 47.56) and 2LV% (14.10; 6.95) in women. Women presented increased CSM in response to postural change and had higher CVM and lower CSM than men in the supine position. In conclusion, women in the age range studied presented a more appropriate response to a postural change than men, suggesting that cardiac autonomic modulation may be better preserved in women than in men.

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.

Aims: The present study evaluated the effects of ovariectomy on heart rate and arterial pressure variability and cardiac baroreflex sensitivity (BRS) in female spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY)., Main Methods: Sham-surgery animals were used as control. Sixteen weeks after ovariectomy or sham-surgery, animals were recorded. Time series of pulse interval (PI) and systolic AP (SAP) were analyzed by means of autoregressive spectral analysis, which quantifies the power of very low (VLF=0.01-0.25 Hz), low (LF=0.25-0.75 Hz) and high frequency (HF=0.75-2.5 Hz) bands. BRS was assessed by means of linear regression between changes of PI and SAP induced by vasoactive drugs or calculation of alpha-index, a spontaneous BRS index., Key Findings: There was no difference in baseline PI or SAP between ovariectomized and sham SHR. Spectral analysis of heart rate variability suggested a shift of sympatho-vagal balance toward sympathetic predominance in ovariectomized SHR (LF/HF=1.8+/-0.2 versus 0.7+/-0.2 in sham SHR, p<0.05). Ovariectomy increased total variance and VLF power of SAP in SHR (29.1+/-9.6 mmHg2 and 18.6+/-6.3 mmHg2 versus 9.1+/-2.1 mmHg2 and 4.3+/-1.4 mmHg2, respectively, in sham SHR, p<0.05). In addition, ovariectomy reduced reflex bradycardia in SHR (0.18+/-0.03 ms/mmHg versus 0.34+/-0.06 ms/mmHg in sham SHR, p<0.05). Ovariectomy did not affect heart rate and SAP variability or BRS in WKY., Significance: These data showed that ovarian hormones deprivation induced marked changes on cardiovascular control, increasing SAP variability and cardiac sympatho-vagal balance and blunting BRS in female hypertensive animals, which reinforce the possible protective role of ovarian hormones on the cardiovascular system.

Neural signals convey information through two different modalities: intensity and discharge pattern. The intensity code is based on the number of action potentials per unit time, which is then easily translated into neurotransmitter release. This kind of information may be assessed simply by counting the number of spikes or bursts over a time unit. However, the discharge pattern is a further, efficient means of neural information transfer. Rhythmic patterns (i.e. oscillations) can support highly structured, temporal codes based on correlation and synchronization. It is therefore clear that applying frequency domain analysis to sympathetic activity recorded in animals and humans may provide additional information about the neural control of the circulation. Over the last century, data obtained by the analysis of sympathetic activity in experimental animals, and recently also in humans, have provided fundamental contributions to our understanding of the physiological mechanisms involved in the neural control of circulation, as well as how these are altered in cardiovascular and non-cardiovascular diseases. The aim of this paper is to address some aspects related to the recording, analysis and interpretation of sympathetic activity in rats and humans, with special emphasis on analysis in the frequency domain.

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.

We exploit time reversibility analysis, checking the invariance of statistical features of a series after time reversal, to detect temporal asymmetries of short-term heart period variability series. Reversibility indexes were extracted from 22 healthy fetuses between 16th to 40th wk of gestation and from 17 healthy humans (aged 21 to 54, median=28) during graded head-up tilt with table inclination angles randomly selected inside the set {15, 30, 45, 60, 75, 90}. Irreversibility analysis showed that nonlinear dynamics observed in short-term heart period variability are mostly due to asymmetric patterns characterized by bradycardic runs shorter than tachycardic ones. These temporal asymmetries were 1) more likely over short temporal scales than over longer, dominant ones; 2) more frequent during the late period of pregnancy (from 25th to 40th week of gestation); 3) significantly present in healthy humans at rest in supine position; 4) more numerous during 75 and 90 degrees head-up tilt. Results suggest that asymmetric patterns observable in short-term heart period variability might be the result of a fully developed autonomic regulation and that an important shift of the sympathovagal balance toward sympathetic predominance (and vagal withdrawal) can increase their presence.

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.

We propose an integrated approach based on uniform quantization over a small number of levels for the evaluation and characterization of complexity of a process. This approach integrates information-domain analysis based on entropy rate, local nonlinear prediction, and pattern classification based on symbolic analysis. Normalized and non-normalized indexes quantifying complexity over short data sequences ( approximately 300 samples) are derived. This approach provides a rule for deciding the optimal length of the patterns that may be worth considering and some suggestions about possible strategies to group patterns into a smaller number of families. The approach is applied to 24 h Holter recordings of heart period variability derived from 12 normal (NO) subjects and 13 heart failure (HF) patients. We found that: (i) in NO subjects the normalized indexes suggest a larger complexity during the nighttime than during the daytime; (ii) this difference may be lost if non-normalized indexes are utilized; (iii) the circadian pattern in the normalized indexes is lost in HF patients; (iv) in HF patients the loss of the day-night variation in the normalized indexes is related to a tendency of complexity to increase during the daytime and to decrease during the nighttime; (v) the most likely length L of the most informative patterns ranges from 2 to 4; (vi) in NO subjects classification of patterns with L=3 indicates that stable patterns (i.e., those with no variations) are more present during the daytime, while highly variable patterns (i.e., those with two unlike variations) are more frequent during the nighttime; (vii) during the daytime in HF patients, the percentage of highly variable patterns increases with respect to NO subjects, while during the nighttime, the percentage of patterns with one or two like variations decreases.

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.

This paper evaluates the paradigm that proposes to quantify short-term complexity and detect nonlinear dynamics by exploiting local nonlinear prediction. Local nonlinear prediction methods are classified according to how they judge similarity among patterns of L samples (i.e., according to different definitions of the cells utilized to discretize the phase space) and examined in connection with different types of surrogate data: 1) phase-randomized or Fourier transform based, FT; 2) amplitude-adjusted FT, AAFT; 3) iteratively-refined AAFT, IAAFT, preserving distribution IAAFT-1; 4) IAAFT preserving power spectrum, IAAFT-2. The methods were applied on ad-hoc simulations and on a large database of short heart period variability series (approximately 300 cardiac beats) recorded in healthy young subjects during experimental conditions inducing a sympathetic activation (head-up tilt, infusion of nitroprusside, or handgrip), a parasympathetic activation (low dose administration of atropine or infusion of phenylephrine), a complete parasympathetic blockade (high dose administration of atropine), or during controlled respiration at different breathing rates. As to complexity analysis we found that: 1) although complexity indexes derived from different methods were different in terms of absolute values, changes due to experimental conditions were consistently detected; 2) complexity was significantly decreased by all the experimental conditions provoking a sympathetic activation and by controlled respiration at slow breathing rates. As to detection of nonlinearities we found that: 1) IAAFT-1 and IAAFT-2 surrogates performed similarly in all protocols; 2) FT and IAAFT surrogates detected about the same percentage of nonlinear dynamics in all protocols; 3) AAFT surrogates were inappropriate with all the methods and should be dismissed in future applications; 4) methods based on overlapping cells with variable size were characterized by a larger rate of false detections of nonlinear dynamics; 5) short-term heart period variability at rest was mostly linear; 6) controlled respiration at slow breathing rates increased nonlinear components, while the separate activation of the two branches of the autonomic nervous system (i.e., sympathetic or parasympathetic) was ineffective at this regard.

We evaluated the role played by the autonomic nervous system in producing non-linear dynamics in short heart period variability (HPV) series recorded in healthy young humans. Non-linear dynamics are detected using an index of predictability based on a local non-linear predictor and a surrogate data approach. Different types of surrogates are utilized: (i) phase-randomized Fourier-transform based (FT) data; (ii) amplitude-adjusted FT (AAFT) data; and (iii) iteratively refined AAFT (IAAFT) data of two types (IAAFT-1 and IAAFT-2). The approach was applied to experimental protocols activating or blocking the sympathetic or parasympathetic branches of the autonomic nervous system or periodically perturbing cardiovascular control via paced respiration at different breathing rates. We found that short-term HPV was mostly linear at rest. Experimental protocols activating the sympathetic or parasympathetic nervous system did not produce non-linear dynamics. In contrast, paced respiration, especially at slow breathing rates, elicited significantly non-linear dynamics. Therefore, in short-term HPV ( approximately 300 beats) the use of non-linear models is not supported by the data, except under conditions whereby the subject is constrained to a slow respiratory rate.

The goal of this study was to determine the baroreflex influence on systolic arterial pressure (SAP) and pulse interval (PI) variability in conscious mice. SAP and PI were measured in C57Bl/6J mice subjected to sinoaortic deafferentation (SAD, n = 21) or sham surgery (n = 20). Average SAP and PI did not differ in SAD or control mice. In contrast, SAP variance was enhanced (21 +/- 4 vs. 9.5 +/- 1 mmHg2) and PI variance reduced (8.8 +/- 2 vs. 26 +/- 6 ms2) in SAD vs. control mice. High-frequency (HF: 1-5 Hz) SAP variability quantified by spectral analysis was greater in SAD (8.5 +/- 2.0 mmHg2) compared with control (2.5 +/- 0.2 mmHg2) mice, whereas low-frequency (LF: 0.1-1 Hz) SAP variability did not differ between the groups. Conversely, LF PI variability was markedly reduced in SAD mice (0.5 +/- 0.1 vs. 10.8 +/- 3.4 ms2). LF oscillations in SAP and PI were coherent in control mice (coherence = 0.68 +/- 0.05), with changes in SAP leading changes in PI (phase = -1.41 +/- 0.06 radians), but were not coherent in SAD mice (coherence = 0.08 +/- 0.03). Blockade of parasympathetic drive with atropine decreased average PI, PI variance, and LF and HF PI variability in control (n = 10) but had no effect in SAD (n = 6) mice. In control mice, blockade of sympathetic cardiac receptors with propranolol increased average PI and decreased PI variance and LF PI variability (n = 6). In SAD mice, propranolol increased average PI (n = 6). In conclusion, baroreflex modulation of PI contributes to LF, but not HF PI variability, and is mediated by both sympathetic and parasympathetic drives in conscious mice.

Heart failure is associated with autonomic imbalance, and this can be evaluated by a spectral analysis of heart rate variability. However, the time course of low-frequency (LF) and high-frequency (HF) heart rate variability changes, and their functional correlates during progression of the disease are not exactly known. Progressive heart failure was induced in 16 beagle dogs over a 7-wk period by rapid ventricular pacing. Spectral analysis of heart rate variability and respiration, echocardiography, hemodynamic measurements, plasma atrial natriuretic factor, and norepinephrine was obtained at baseline and every week, 30 min after pacing interruption. Progressive heart failure increased heart rate (from 91 +/- 4 to 136 +/- 5 beats/min; P < 0.001) and decreased absolute and normalized (percentage of total power) HF variability from week 1 and 2, respectively (P < 0.01). Absolute LF variability did not change during the study until it disappeared in two dogs at week 7 (P < 0.05). Normalized LF variability increased in moderate heart failure (P < 0.01), leading to an increased LF-to-HF ratio (P < 0.05), but decreased in severe heart failure (P < 0.044; week 7 vs. week 5). Stepwise regression analysis revealed that among heart rate variables, absolute HF variability was closely associated with wedge pressure, right atrial and pulmonary arterial pressure, left ventricular ejection fraction and volume, ratio of maximal velocity of early (E) and atrial (A) mitral flow waves, left atrial diameter, plasma norepinephrine, and atrial natriuretic peptide (0.45 < r < 0.65, all P < 0.001). In tachycardia-induced heart failure, absolute HF heart rate variability is a more reliable indicator of cardiac dysfunction and neurohumoral activation than LF heart rate variability.

Background: Sympathetic and parasympathetic systems are considered the principal rapidly reacting systems that control heart rate., Methods and Results: We propose a symbolic analysis series to quantify the prevalence of sympathetic or parasympathetic cardiac modulation. This analysis decomposes the heart rate variability series in patterns lasting 3 beats and classifies them into 3 categories: nonvariable, variable, and very variable patterns referred to as 0V, 1V, and 2V patterns. First, we applied this method to experimental and pharmacological conditions characterized by sympathetic activation (tilt test, handgrip, nitroprusside, and high-dose atropine administration) or parasympathetic activation (phenylephrine and low-dose atropine administration) in 60 healthy subjects. An increase in sympathetic modulation and a vagal withdrawal elicited a significant increase in 0V patterns and a decrease in 2V patterns, whereas parasympathetic dominance induced the opposite, reflecting a reciprocal sympathovagal balance. The second part of the study considered a series of 300 beats before the onset of major arrhythmic events in patients with an implantable cardioverter-defibrillator. Symbolic analysis detected an increase in the percentage of 0V patterns before the onset of major arrhythmias compared with baseline (41.6+/-3.9% and 24.4+/-2.9%, respectively; P<0.01), indicating a sympathetic prevalence. On the other hand, the 2V patterns did not decrease before major arrhythmias, suggesting the presence of nonreciprocal autonomic modulations., Conclusions: Symbolic analysis of 3 beat sequences takes into account the different time course of sympathetic and parasympathetic cardiac modulations and seems appropriate for elucidating the neural pathophysiological mechanisms occurring during the short periods that precede acute cardiac events.

Objective: We introduce an algorithm for the automatic decomposition of Wigner Distribution (WD) and we applied it for the quantitative extraction of Heart Rate Variability (HRV) spectral parameters during non-stationary events. Early response to tilt was investigated., Methods: Quantitative analysis of multi-components non-stationary signals is obtained through an automatic decomposition of WD based on least square (LS) fitting of the instantaneous autocorrelation function (ACF). Through this approach the different signal and interference terms which contributes to the ACF may be separated and their parameters (instantaneous frequency and amplitude) quantified. A beat-to-beat monitoring of HRV spectral components is obtained., Results: Analysis of simulated signals demonstrated the capability of the proposed approach to track and separate the signal components. Analysis of HRV data evidenced different dynamics in the early Autonomic Nervous System (ANS) response to tilt., Conclusions: The novel approach to the quantification of the beat-to-beat HRV spectral parameters obtained from decomposition of Wigner distribution was demonstrated to be effective in the analysis of HRV data. Relevant physiological information about the dynamics of the early sympathetic response to tilt were obtained. The method is a general approach which may be employed for a quantitative time-frequency analysis of non-stationary biological signals.

Power spectrum analysis of cardiovascular signal variability, and in particular of the RR period (heart rate variability), is a widely used procedure for the investigation of autonomic cardiovascular control and/or target function impairment. However, a correct methodology is essential to extract the information embedded in the frequency domain. This article has the main purpose of proposing a still wider clinical use of the spectral methodology. Indeed, with this procedure the state of the sympathovagal balance modulating the sinus node pacemaker activity can be quantified in a variety of physiological and pathophysiological conditions. Changes in the 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.

An integrated approach to the complexity analysis of short heart period variability series (approximately 300 cardiac beats) is proposed and applied to healthy subjects during the sympathetic activation induced by head-up tilt and during the driving action produced by controlled respiration (10, 15, and 20 breaths/min, CR10, CR15, and CR20 respectively). The approach relies on: 1) the calculation of Shannon entropy (SE) of the distribution of patterns lasting three beats; 2) the calculation of a regularity index based on an entropy rate (i.e., the conditional entropy); 3) the classification of frequent deterministic patterns (FDPs) lasting three beats. A redundancy reduction criterion is proposed to group FDPs in four categories according to the number and type or of heart period changes: a) no variation (0V); b) one variation (1V); and c) two like variations (2LV); 4) two unlike variations (2UV). We found that: 1) the SE decreased during tilt due to the increased percentage of missing patterns; 2) the regularity index increased during tilt and CR10 as patterns followed each other according to a more repetitive scheme; and 3) during CR10, SE and regularity index were not redundant as the regularity index significantly decreased while SE remained unchanged. Concerning pattern analysis we found that: a) at rest mainly three classes (0V, 1V, and 2LV) were detected; b) 0V patterns were more likely during tilt; c) 1V and 2LV patterns were more frequent during CR10; and d) 2UV patterns were more likely during CR20. The proposed approach based on quantification of complexity allows a full characterization of heart period dynamics and the identification of experimental conditions known to differently perturb cardiovascular regulation.

Spectral analysis of heart rate and arterial pressure variabilities is a powerful noninvasive tool, which is increasingly used to infer alterations of cardiovascular autonomic regulation in a variety of physiological and pathophysiological conditions, such as hypertension, myocardial infarction and congestive heart failure. A most important methodological issue to properly interpret the results obtained by the spectral analysis of cardiovascular variability signals is represented by the attribution of neurophysiological correlates to these spectral components. In this regard, recent applications of spectral techniques to the evaluation of the oscillatory properties of sympathetic efferent activity in animals, as well as in humans, offer a new approach to a better understanding of the relationship between cardiovascular oscillations and autonomic regulation.

Chemoreflex stimulation elicits both hyperventilation and sympathetic activation, each of which may have different influences on oscillatory characteristics of cardiovascular variability. We examined the influence of hyperventilation on the interactions between changes in R-R interval (RR) and muscle sympathetic nerve activity (MSNA) and changes in neurocirculatory variability, in 14 healthy subjects. We performed spectral analysis of RR and MSNA variability during each of the following interventions: 1) controlled breathing, 2) maximal end-expiratory apnea, 3) isocapnic voluntary hyperventilation, and 4) hypercapnia-induced hyperventilation. MSNA increased from 100% during controlled breathing to 170 +/- 25% during apnea (P = 0.02). RR was unchanged, but normalized low-frequency (LF) variability of both RR and MSNA increased markedly (P < 0.001). During isocapnic hyperventilation, minute ventilation increased to 20.2 +/- 1.4 l/min (P < 0.0001). During hypercapnic hyperventilation, minute ventilation also increased (to 19.7 +/- 1.7 l/min) as did end-tidal CO(2) (both P < 0.0001). MSNA remained unchanged during isocapnic hyperventilation (104 +/- 7%) but increased to 241 +/- 49% during hypercapnic hyperventilation (P < 0.01). RR decreased during both isocapnic and hypercapnic hyperventilation (P < 0.05). However, normalized LF variability of RR and of MSNA decreased (P < 0.05) during both isocapnic and hypercapnic hyperventilation, despite the tachycardia and heightened sympathetic nerve traffic. In conclusion, marked respiratory oscillations in autonomic drive induced by hyperventilation may induce dissociation between RR, MSNA, and neurocirculatory variability, perhaps by suppressing central genesis and/or inhibiting transmission of LF cardiovascular rhythms.

Interactions between mechanisms governing ventilation and blood pressure (BP) are not well understood. We studied in 11 resting normal subjects the effects of sustained isocapnic hyperventilation on arterial baroreceptor sensitivity, determined as the alpha index between oscillations in systolic BP (SBP) generated by respiration and oscillations present in R-R intervals (RR) and in peripheral sympathetic nerve traffic [muscle sympathetic nerve activity (MSNA)]. Tidal volume increased from 478 +/- 24 to 1,499 +/- 84 ml and raised SBP from 118 +/- 2 to 125 +/- 3 mmHg, whereas RR decreased from 947 +/- 18 to 855 +/- 11 ms (all P < 0.0001); MSNA did not change. Hyperventilation reduced arterial baroreflex sensitivity to oscillations in SBP at both cardiac (from 13 +/- 1 to 9 +/- 1 ms/mmHg, P < 0.001) and MSNA levels (by -37 +/- 5%, P < 0.0001). Thus increased BP during hyperventilation does not elicit any reduction in either heart rate or MSNA. Baroreflex modulation of RR and MSNA in response to hyperventilation-induced BP oscillations is attenuated. Blunted baroreflex gain during hyperventilation may be a mechanism that facilitates simultaneous increases in BP, heart rate, and sympathetic activity during dynamic exercise and chemoreceptor activation.