Concomitant Evaluation of Heart Period and QT Interval Variability Spectral Markers to Typify Cardiac Control in Humans and Rats.

The variability of heart period, measured as the time distance between two consecutive QRS complexes from the electrocardiogram (RR), was exploited to infer cardiac vagal control, while the variability of the duration of the electrical activity of the heart, measured as the time interval from Q-wave onset to T-wave end (QT), was proposed as an indirect index of cardiac sympathetic modulation. This study tests the utility of the concomitant evaluation of RR variability (RRV) and QT variability (QTV) markers in typifying cardiac autonomic control of humans under different experimental conditions and of rat groups featuring documented differences in resting sympatho-vagal balance. We considered: (i) 23 healthy young subjects in resting supine position (REST) undergoing head-up tilt at 45° (T45) and 90° (T90) followed by recovery to the supine position; (ii) 9 Wistar (WI) and 14 wild-type Groningen (WT) rats in unstressed conditions, where the WT animals were classified as non-aggressive (non-AGG, n = 9) and aggressive (AGG, n = 5) according to the resident intruder test. In humans, spectral analysis of RRV and QTV was performed over a single stationary sequence of 250 consecutive values. In rats, spectral analysis was iterated over 10-min recordings with a frame length of 250 beats with 80% overlap and the median of the distribution of the spectral markers was extracted. Over RRV and QTV we computed the power in the low frequency (LF, from 0.04 to 0.15 Hz in humans and from 0.2 to 0.75 Hz in rats) band (LFRR and LFQT) and the power in the high frequency (HF, from 0.15 to 0.5 Hz in humans and from 0.75 to 2.5 Hz in rats) band (HFRR and HFQT). In humans the HFRR power was lower during T90 and higher during recovery compared to REST, while the LFQT power was higher during T90. In rats the HFRR power was lower in WT rats compared to WI rats and the LFQT power was higher in AGG than in non-AGG animals. We concluded that RRV and QTV provide complementary information in describing the functioning of vagal and sympathetic limbs of the autonomic nervous system in humans and rats.

Comparison of Causal and Non-causal Strategies for the Assessment of Baroreflex Sensitivity in Predicting Acute Kidney Dysfunction After Coronary Artery Bypass Grafting.

Coronary artery bypass graft (CABG) surgery may lead to postoperative complications such as the acute kidney dysfunction (AKD), identified as any post-intervention increase of serum creatinine level. Cardiovascular control reflexes like the baroreflex can play a role in the AKD development. The aim of this study is to test whether baroreflex sensitivity (BRS) estimates derived from non-causal and causal approaches applied to spontaneous systolic arterial pressure (SAP) and heart period (HP) fluctuations can help in identifying subjects at risk of developing AKD after CABG and which BRS estimates provide the best performance. Electrocardiogram and invasive arterial pressure were acquired from 129 subjects (67 ± 10 years, 112 males) before (PRE) and after (POST) general anesthesia induction with propofol and remifentanil. Subjects were divided into AKDs (n = 29) or no AKDs (noAKDs, n = 100) according to the AKD development after CABG. The non-causal approach assesses the transfer function from the HP-SAP cross-spectrum in the low frequency (LF, 0.04-0.15 Hz) band. BRS was estimated according to three strategies: (i) sampling of the transfer function gain at the maximum of the HP-SAP squared coherence in the LF band; (ii) averaging of the transfer function gain in the LF band; (iii) sampling of the transfer function gain at the weighted central frequency of the spectral components of the SAP series dropping in the LF band. The causal approach separated the two arms of cardiovascular control (i.e., from SAP to HP and vice versa) and accounted for the confounding influences of respiration via system identification and modeling techniques. The causal approach provided a direct estimate of the gain from SAP to HP by observing the HP response to a simulated SAP rise from the identified model structure. Results show that BRS was significantly lower in AKDs than noAKDs during POST regardless of the strategy adopted for its computation. Moreover, all the BRS estimates during POST remained associated with AKD even after correction for demographic and clinical factors. Non-causal and causal BRS estimates exhibited similar performances. Baroreflex impairment is associated with post-CABG AKD and both non-causal and causal methods can be exploited to improve risk stratification of AKD after CABG.

Cardiac baroreflex hysteresis is one of the determinants of the heart period variability asymmetry.

In heart period (HP) variability (HPV) recordings the percentage of negative HP variations tends to be greater than that of positive ones and this pattern is referred to as HPV asymmetry (HPVA). HPVA has been studied in several experimental conditions in healthy and pathological populations, but its origin is unclear. The baroreflex (BR) exhibits an asymmetric behavior as well given that it reacts more importantly to positive than negative arterial pressure (AP) variations. We tested the hypothesis that the BR asymmetry (BRA) is a HPVA determinant over spontaneous fluctuations of HP and systolic AP (SAP). We studied 100 healthy subjects (age from 21 to 70 yr, 54 men) comprising 20 subjects in each age decade. Electrocardiogram and noninvasive AP were recorded for 15 min at rest in supine position (REST) and during active standing (STAND). The HPVA was evaluated via Porta's index and Guzik's index, while the BRA was assessed as the difference, and normalized difference, between BR sensitivities computed over positive and negative SAP variations via the sequence method applied to HP and SAP variability. HPVA significantly increased during STAND and decreased progressively with age. BRA was not significantly detected both at REST and during STAND. However, we found a significant positive association between BRA and HPVA markers during STAND persisting even within the age groups. This study supports the use of HPVA indexes as descriptors of BRA and identified a challenge soliciting the BR response like STAND to maximize the association between HPVA and BRA markers.

Acute Fingolimod Effects on Baroreflex and Cardiovascular Autonomic Control in Multiple Sclerosis.

BACKGROUND: Fingolimod, an oral drug used in multiple sclerosis (MS) treatment, exerts its action through S1P-receptor engagement. These receptors are also expressed in heart and endothelial cells. The engagement of receptors on the atrial heart myocytes may cause a slowing effect on heart rate (HR). We aimed to explore the acute effect of fingolimod on the cardiac autonomic control, a side-effect of the drug that still needs to be clarified. METHODS: In 10 MS patients, we investigated the influence of the first administration of fingolimod (0.5 mg) on sympathetic and parasympathetic indexes via the analysis of the HR variability, and on the baroreflex sensitivity via sequence and alpha coefficient techniques. RESULTS: Fingolimod produced an average HR maximal drop of 12.7 (7.8) beats/min and the minimal HR occurred after 2.73 (0.38) hours from the dose administration. The pulse interval (PI) mean value and the pNN50 and RMSSD indexes of parasympathetic drive to the heart significantly increased. Interestingly, in 6 out of 10 patients also the power in the low-frequency band (LF) increased. The baroreflex sensitivity was not modified by the first dose of the drug. CONCLUSIONS: Our findings indicate that although the first dose of fingolimod invariably activates the parasympathetic system, in several subjects, it may induce also a surge in the sympathetic cardiac drive. This suggests that not only the vagal, as usually assumed, but also the sympathetic autonomic branch should be considered in the risk profile assessment of MS patients starting treatment with fingolimod.

Causality analysis reveals the link between cerebrovascular control and acute kidney dysfunction after coronary artery bypass grafting.

BACKGROUND: Patients undergoing coronary artery bypass graft (CABG) surgery might experience postoperative complications and some of them, such as acute kidney dysfunction (AKD), are the likely consequence of hypoperfusion. We hypothesized that an impaired cerebrovascular control is a hallmark of a vascular damage that might favor AKD after CABG. OBJECTIVE: Our aim is to characterize cerebrovascular control in CABG patients through the assessment of the relationship between mean arterial pressure (MAP) and mean cerebral blood flow velocity (MCBFV) and to check whether markers describing MCBFV-MAP dynamical interactions could identify subjects at risk to develop postoperative AKD. APPROACH: MAP and MCBFV beat-to-beat series were extracted from invasive arterial pressure and transcranial Doppler recordings acquired simultaneously in 23 patients just before CABG after the induction of propofol general anesthesia. Subjects were divided into AKD group (n = 9, age: 68 ± 9, 8 males) and noAKD group (n = 14, age: 65 ± 8, 12 males) according to whether they developed postoperative AKD or not after CABG. We computed MAP and MCBFV time-domain and spectral markers as well as MCBFV-MAP cross-spectral indexes in very-low-frequency (VLF, 0.02-0.07 Hz), low-frequency (LF, 0.07-0.15 Hz) and high-frequency (HF, 0.15-0.30 Hz) bands. We also calculated model-based transfer entropy (TE) to quantify the degree of MCBFV dependence on MAP and vice versa. The null hypothesis of MCBFV-MAP uncoupling was tested via a surrogate approach associating MAP and MCBFV in different patients. MAIN RESULTS: Time, spectral and cross-spectral markers had a limited power in separating AKD from noAKD individuals. Conversely, TE from MAP to MCBFV was significantly above the level set by surrogates only in AKD groups and significantly larger than that computed in noAKD. SIGNIFICANCE: The reduced cerebrovascular autoregulation in AKD patients suggest a vascular impairment likely making them more at risk of hypoperfusion during CABG and AKD after CABG.

Characterization of the Asymmetry of the Cardiac and Sympathetic Arms of the Baroreflex From Spontaneous Variability During Incremental Head-Up Tilt.

Hysteresis of the baroreflex (BR) is the result of the different BR sensitivity (BRS) when arterial pressure (AP) rises or falls. This phenomenon has been poorly studied and almost exclusively examined by applying pharmacological challenges and static approaches disregarding causal relations. This study inspects the asymmetry of the cardiac BR (cBR) and vascular sympathetic BR (sBR) in physiological closed loop conditions from spontaneous fluctuations of physiological variables, namely heart period (HP) and systolic AP (SAP) leading to the estimation of cardiac BRS (cBRS) and muscle sympathetic nerve activity (MSNA) and diastolic AP (DAP) leading to the estimation of vascular sympathetic BRS (sBRS). The assessment was carried out in 12 young healthy subjects undergoing incremental head-up tilt with table inclination gradually increased from 0 to 60°. Two analytical methods were exploited and compared, namely the sequence (SEQ) and phase-rectified signal averaging (PRSA) methods. SEQ analysis is based on the detection of joint causal schemes representing the HP and MSNA burst rate delayed responses to spontaneous SAP and DAP modifications, respectively. PRSA analysis averages HP and MSNA burst rate patterns after aligning them according to the direction of SAP and DAP changes, respectively. Since cBRSs were similar when SAP went up or down, hysteresis of cBR was not detected. Conversely, hysteresis of sBR was evident with sBRS more negative when DAP was falling than rising. sBR hysteresis was no longer visible during sympathetic activation induced by the orthostatic challenge. These results were obtained via the SEQ method, while the PRSA technique appeared to be less powerful in describing the BR asymmetry due to the strong association between BRS estimates computed over positive and negative AP variations. This study suggests that cBR and sBR provide different information about the BR control, sBR exhibits more relevant non-linear features that are evident even during physiological changes of AP, and the SEQ method can be fruitfully exploited to characterize the BR hysteresis with promising applications to BR branches different from cBR and sBR.

Short-term multiscale complexity analysis of cardiovascular variability improves low cardiac output syndrome risk stratification after coronary artery bypass grafting.

BACKGROUND: Low cardiac output syndrome (LCOS) is a myocardial dysfunction leading to systemic hypoperfusion, favored by particular conditions of the autonomic nervous system. LCOS is one of the adverse events that might occur after cardiac surgery. OBJECTIVE: The aim is to test the hypothesis that short-term multiscale complexity (MSC) analysis of heart period (HP) and systolic arterial pressure (SAP) variability series in the frequency bands typical of cardiovascular control could be fruitfully exploited in identifying subjects at risk of developing LCOS after coronary artery bypass graft (CABG). APPROACH: HP and SAP beat-to-beat series were derived from electrocardiogram (ECG) and invasive arterial pressure (AP) signal acquired in 128 patients scheduled for CABG before (PRE) and after (POST) the induction of general anesthesia with propofol and remifentanil. Subjects were labeled as LCOS (n = 14) and noLCOS (n = 114) according to the LCOS development. MSC markers were calculated as the complement to 1 of the modulus of the average position of the poles dropping in the low-frequency (LF, 0.04-0.15 Hz) and high-frequency (HF, 0.15-0.5 Hz) bands as derived from the autoregressive model of HP and SAP series. Traditional time and frequency domain indexes were also calculated. MAIN RESULTS: Traditional parameters were able to assess the depression of the cardiovascular regulation induced by general anesthesia, but showed weak performances in differentiating LCOS and noLCOS groups. Conversely, HP complexity in LF band and SAP complexity in HF band assessed during POST remained associated with LCOS even after entering a multivariate logistic regression model adjusted for clinical and demographic factors. SIGNIFICANCE: The MSC approach can be fruitfully applied to improve risk stratification for LCOS after CABG likely because MSC markers describe the dysfunction of the sympathetic control and the impairment of the mechanical properties of the heart in the LCOS group.

Information-domain method for the quantification of the complexity of the sympathetic baroreflex regulation in healthy subjects and amyotrophic lateral sclerosis patients.

BACKGROUND: The sympathetic baroreflex (sBR) adjusts muscle sympathetic nerve activity (MSNA) in response to arterial pressure changes but the relevance of assessing sBR control complexity is unclear. OBJECTIVE: We propose a method for the evaluation of sBR control complexity. APPROACH: The approach comprises the quantification of complexity of the sBR latency regulation and the assessment of complexity of the relationship linking MSNA burst to R-wave peak regardless of the variability of the sBR latency. The Shannon entropy (SE) of the sBR latency distribution is taken as an estimate of complexity of the sBR latency regulation. The conditional entropy (CE) of the beat-to-beat binary series obtained by coding the presence/absence of the MSNA burst after an R-wave peak is taken as an estimate of complexity of the sBR control regardless of the sBR latency variability. Surrogate analysis was utilized to set the level of inactive or impaired sBR. The approach was applied to 10 young healthy subjects undergoing head-up tilt (HUT) followed by lower body negative pressure to evoke presyncope (preSYNC) before and after 21 d head-down bed rest (HDBR), and to five amyotrophic lateral sclerosis (ALS) patients undergoing HUT. MAIN RESULTS: In healthy subjects the surrogate analysis suggested that HUT and preSYNC significantly activated the sBR control but its response was weakened after 21 d HDBR. During preSYNC sBR latency increased significantly only after 21 d HDBR. In ALS patients the complexity of the sBR latency regulation was close to the level set by surrogate analysis and HUT did not trigger any sBR control response. SIGNIFICANCE: The proposed method for sBR control complexity quantification was useful in detecting the impairment of the sBR control after 21 d HDBR in healthy subjects and the dysfunction of the sBR regulation in ALS patients.

On the Relevance of Computing a Local Version of Sample Entropy in Cardiovascular Control Analysis.

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

Strength and Latency of the HP-SAP Closed Loop Variability Interactions in Subjects Prone to Develop Postural Syncope.

The coupling and latency between heart period (HP) and systolic arterial pressure (SAP) variability can be investigated along the two arms of the HP-SAP closed loop, namely along the baroreflex feedback from SAP to HP, and along the feedforward pathway from HP to SAP. This study investigates the HP-SAP closed loop variability interactions through cross-correlation function (CCF). Coupling strength and delay between HP and SAP variability series were monitored in 13 subjects prone to develop orthostatic syncope (SYNC, 28±9 yrs, 5 males) and in 13 subjects with no history of postural syncope (noSYNC, age: 27±8 yrs, 5 males). Analysis was carried out at rest in supine position (REST) and during head-up tilt (TILT) at 60 degrees. The null hypothesis of HP-SAP uncoupling was tested through a surrogate analysis associating the HP series of a subject with a SAP sequence of a different one. Results showed that during TILT the coupling strength increased along the baroreflex and latency augmented along the mechanical feedforward pathway exclusively in noSYNC subjects. Finally, closed loop HP-SAP interactions were detected in about one third of subjects and the situation of full uncoupling was rarely found. CCF analysis was found to be a straightforward and easily applicable method to investigate HP-SAP control deserving a direct comparison with more sophisticated signal processing tools assessing causality.

Assessment of the Coupling Strength of Cardiovascular Control via Joint Symbolic Analysis during Postural Challenge in Recreational Athletes.

Short-term cardiovascular control, comprising cardiac baroreflex and mechanisms governing cardiac contractility and vascular properties, links heart period (HP) and systolic arterial pressure (SAP) fluctuations. It is activated during postural challenge and this activation is traditionally quantified via linear tools such as HP-SAP squared coherence function. In this study the ability of a nonlinear bivariate tool based on joint symbolic analysis (JSA) approach was tested against HP-SAP coherence function during orthostatic challenge in recreational athletes. We studied 9 men healthy cycling practitioners (age: 20-40 yrs) at rest in supine condition (REST) and during active standing (STAND). The JSA method is based on the definition of symbolic HP and SAP patterns and on the evaluation of the rate of their simultaneous occurrence in both HP and SAP series. HP-SAP squared coherence was computed in the low frequency band (LF, from 0.04 to 0.15 Hz). We found the expected response to the postural stimulus, namely the increase of sympathetic modulation and the contemporaneous vagal withdrawal. However, only JSA was able to detect the expected increase of association between HP and SAP variability series over slow time scales. This result suggests that recreational athletes have more relevant nonlinear interactions between HP and SAP that might be missed by traditional linear tools and might require nonlinear tools to be efficiently described.

Assessing Synergy/Redundancy of Baroreflex and Non-Baroreflex Components of the Cardiac Control during Sleep.

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

Comparison of Different Strategies to Assess Cardiac Baroreflex Sensitivity Based on Transfer Function Technique in Patients Undergoing General Anesthesia.

Baroreflex sensitivity (BRS) can be noninvasively assessed from heart period (HP) and arterial pressure (AP) variability series via the estimation of the gain of the transfer function (TF) in the low frequency (LF, 0.04-0.15 Hz) band. However, different strategies can be adopted to pick the value of the TF gain and different fiducial AP values can be considered. In this study we compared different strategies to reduce the TF gain into a unique maker: i) sampling the TF gain in correspondence of the maximum of the HP-AP squared coherence; ii) sampling the TF gain at the weighted average of the central frequencies of AP spectral components; iii) calculating the average of the TF gain in the LF band. Indexes were computed using alternatively systolic AP (SAP) or diastolic AP (DAP) series in combination with HP. Results were obtained in 129 patients undergoing coronary artery bypass graft surgery before (PRE) and after (POST) the induction of general anesthesia with propofol and remifentanil. The reduction of BRS during general anesthesia is expected as a result of overall depression of the cardiovascular control even in this group of pathological subjects already featuring a low BRS before general anesthesia induction. We found that the expected decrease of BRS was observed regardless of the strategy using DAP. Moreover, regardless of series (i.e., SAP or DAP), the sampling of TF gain at the weighted average of the central frequencies of the AP spectral components has the greatest statistical power in distinguishing the two experimental conditions. We recommend the use of this strategy in assessing BRS via TF analysis and a more frequent exploitation of the DAP series.

Short-Term Model-Based Multiscale Complexity Analysis of Cardiac Control Provides Complementary Information to Single-Scale Approaches.

The study compares a recently proposed shortterm model-based linear multiscale complexity approach to a single-scale application of the same method and to a model-free nonlinear one based on the computation of conditional entropy with the aim at assessing the complementary information. Comparison was carried out over 24 hours Holter recordings of heart period variability during daytime and nighttime in 12 healthy men (age: 34-55 years). Single-scale methods were able to detect the increased complexity of the cardiac control during nighttime. Multiscale complexity analysis showed that this increase was due to an increase of complexity in the low frequency band (from 0.04 to 0.15 Hz), while complexity in the range of frequencies typical of the respiratory rate was unmodified. Regardless of the method (i.e. linear or nonlinear) single-scale complexity indexes were uncorrelated to the multiscale ones. We conclude that short-term model-based linear multiscale complexity approach provides complementary information to single-scale methods in an application devoted to the analysis of cardiac control from 24 hours Holter recordings.

Comparison between probabilistic and Wiener-Granger causality in assessing modifications of the cardiac baroreflex control with age.

BACKGROUND: Probabilistic causality (PC) is a framework for checking that the occurrence of a cause raises the probability of the effect by comparing the probability of the effect conditioned and unconditioned to the cause. Even though it is less frequently utilized with respect to the more traditional model-based Wiener-Granger causality (WGC) that is based on the predictability improvement of an effect resulting from the inclusion of the presumed cause in the multivariate linear regression model, PC has the advantage of being model-free. OBJECTIVE: The aim of the study is to apply the PC framework to assess the evolution of cardiac baroreflex control with age from spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) and to compare it to the more common WGC approach. APPROACH: We studied 100 healthy humans (54 males, age: 21-70 years, 20 subjects for each 10 years bin). HP and SAP were extracted on a beat-to-beat basis from 5 min recordings of electrocardiogram and plethysmographic arterial pressure at rest in supine position (REST) and during active standing (STAND) under spontaneous breathing. The WGC ratio (WGCR) was computed as the log ratio of the prediction error variance of the autoregressive model on HP to that on HP with exogenous SAP. The PC ratio (PCR) was computed as the probability of observing an HP ramp given an associated parallel SAP variation divided by the probability of observing an HP ramp. MAIN RESULTS: The WGCR and PCR suggested the gradual impairment of cardiac baroreflex with age, especially during STAND. Moreover, they were significantly associated both at REST and during STAND but the degree of the PCR-WGCR association was weak. SIGNIFICANCE: PC can be effectively exploited to assess modification of the cardiovascular control during senescence even though a limited agreement was observed with WGC.

Peripheral Resistance Baroreflex During Incremental Bicycle Ergometer Exercise: Characterization and Correlation With Cardiac Baroreflex.

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

Paced Breathing Increases the Redundancy of Cardiorespiratory Control in Healthy Individuals and Chronic Heart Failure Patients.

Synergy and redundancy are concepts that suggest, respectively, adaptability and fault tolerance of systems with complex behavior. This study computes redundancy/synergy in bivariate systems formed by a target X and a driver Y according to the predictive information decomposition approach and partial information decomposition framework based on the minimal mutual information principle. The two approaches assess the redundancy/synergy of past of X and Y in reducing the uncertainty of the current state of X. The methods were applied to evaluate the interactions between heart and respiration in healthy young subjects (n = 19) during controlled breathing at 10, 15 and 20 breaths/minute and in two groups of chronic heart failure patients during paced respiration at 6 (n = 9) and 15 (n = 20) breaths/minutes from spontaneous beat-to-beat fluctuations of heart period and respiratory signal. Both methods suggested that slowing respiratory rate below the spontaneous frequency increases redundancy of cardiorespiratory control in both healthy and pathological groups, thus possibly improving fault tolerance of the cardiorespiratory control. The two methods provide markers complementary to respiratory sinus arrhythmia and the strength of the linear coupling between heart period variability and respiration in describing the physiology of the cardiorespiratory reflex suitable to be exploited in various pathophysiological settings.

An algorithm for the beat-to-beat assessment of cardiac mechanics during sleep on Earth and in microgravity from the seismocardiogram.

Seismocardiogram, SCG, is the measure of precordial vibrations produced by the beating heart, from which cardiac mechanics may be explored on a beat-to-beat basis. We recently collected a large amount of SCG data (>69 recording hours) from an astronaut to investigate cardiac mechanics during sleep aboard the International Space Station and on Earth. SCG sleep recordings are characterized by a prolonged duration and wide heart rate swings, thus a specific algorithm was developed for their analysis. In this article we describe the new algorithm and its performance. The algorithm is composed of three parts: 1) artifacts removal, 2) identification in each SCG waveform of four fiducial points associated with the opening and closure of the aortic and mitral valves, 3) beat-to-beat computation of indexes of cardiac mechanics from the SCG fiducial points. The algorithm was tested on two sleep recordings and yielded the identification of the fiducial points in more than 36,000 beats with a precision, quantified by the Positive Predictive Value, ≥99.2%. These positive findings provide the first evidence that cardiac mechanics may be explored by the automatic analysis of SCG long-lasting recordings, taken out of the laboratory setting, and in presence of significant heart rate modulations.

Fingolimod effects on left ventricular function in multiple sclerosis.

BACKGROUND: Cardiovascular side effects such as bradycardia and atrioventricular block were observed during the early clinical trials of fingolimod in multiple sclerosis, and one cardiovascular- linked death has been reported in the post-marketing period. OBJECTIVE: To investigate the medium-term effects of fingolimod on heart function in order to obtain further insights into its cardiac safety profile. METHODS: The study involved 53 patients starting treatment with fingolimod 0.5 mg daily and 25 patients treated with natalizumab 300 mg monthly. Cardiac function was assessed by means of echocardiography at baseline (T0), and after one (T1), six (T6), and (in the case of the fingolimod group) 12 months (T12). RESULTS: Mean left ventricular ejection fraction significantly decreased and end-systolic volume increased from T0 to T1 (p=0.005) and T6 (p=0.0001) in the fingolimod but not the natalizumab group, although a slight increase was observed at T12. A similar decrease in ejection fraction was also observed after six months in nine patients switched from natalizumab to fingolimod. CONCLUSION: Fingolimod significantly reduces left ventricular systolic function in MS patients. This effect has no clinical consequences in subjects without previous cardiac disorders, but suggests that more caution is required in patients with current or previous heart failure.