Cardiovascular and Respiratory Interactions in Idiopathic Pulmonary Fibrosis by Extended Partial Directed Coherence: Short-term Effects of Supplemental Oxygen.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that can lead to chronic arterial hypoxemia, hypercapnia, and dyspnea. To improve clinical symptoms in IPF patients, supplemental oxygen (SupplO2) has been prescribed with the aim to maintain SpO2 level, and consequently to relieve dyspnea, increase physical activity and improve quality of life. In this study, we investigated the effect of disease and short-term SupplO2 on cardiovascular and respiratory autonomic regulation. Linear and nonlinear indices were extracted from the beat-to-beat variability of heart rate (HR), systolic (SYS) blood pressure and respiration (RESP) in IPF patients and healthy subjects spontaneously breathing ambient air (AA) and during SupplO2 at 3 L/min. It was found that the effects on autonomic nervous systems (ANS) regulation were better demonstrated by the Granger causality (GC) method. GC was significantly higher (p<0.01) in patients compared to controls for the interactions RESP→SYS and BBI→SYS.Clinical Relevance-Short-term SupplO2 in IPF could adversely affect systolic blood pressure variability in particular. This study may help in the management of SupplO2 administration.

Time-Frequency Analysis of Cardiovascular Variability during an Orthostatic Stress by Complete EMD.

Diverse analysis techniques have been used to comprehend the regulation by the autonomic nervous system (ANS) of the cardiovascular system when a human being faces a stressor. Recently, however, the complete ensemble empirical mode decomposition (EMD) with adaptive noise (CEEMDAN) allows analyzing nonstationary signals in a nonlinear and time- variant way. Consequently, CEEMDAN may provide a means to obtain clues about ANS regulation in health and disease. In this study, we analyze the average Hilbert-Huang spectrum (HHS) of cardiovascular variability signals by CEEMDAN during a head-up tilt test (HUTT) in 12 healthy female subjects and 18 orthostatic intolerance female patients. Beat-to-beat intervals (BBI) as well as systolic (SYS) blood pressure variability time series were analyzed. In addition, instantaneous amplitudes and frequencies of specific intrinsic mode functions (IMF) were investigated separately to define the influence of the disease on ANS regulation. Female groups demonstrated statistical differences in the high-frequency band of BBI but higher differences for the high and low-frequency bands of SYS from the mechanical transition of HUTT.Clinical Relevance- A relevant outcome of the study is the average HHS of healthy female subjects along HUTT. This HHS may be used as reference to help diagnose OI when HHS of the cardiovascular variability signals of any subject deviates from the normal course.

Temporal cardiovascular causality during orthostatic stress by extended partial directed coherence.

The aim of this study was to investigate the temporal dynamic behavior of cardiovascular interactions between heart period and systolic blood pressure during a 20-min head-up tilt test at 70° in young women with orthostatic intolerance compared to healthy women. Methods included the lagged and extended partial directed coherence applied to short-term windows shifted by 5 seconds, extracted from a multivariate set of cardiovascular and respiratory time series. Findings revealed significantly increased information flow (p <; 0.01) in patients from: a) heart period to blood pressure during supine position which subsequently decreased and b) blood pressure to heart period during the progression of orthostatic phase. Controls developed balanced cardiovascular interactions with smaller information flows than patients.

Cardiovascular variability in young male and female subjects in health and orthostatic intolerance.

The aim of this study was to investigate the effect of head-up tilt (HUT) test on male and female young patients, diagnosed with orthostatic intolerance (OI), in comparison to male and female healthy subjects. Twenty seven OI patients (21 women, 6 men) and 26 age-matched healthy subjects (13 women, 13 men) were enrolled in a 70° HUT test. In addition to hemodynamic variables, cardiovascular and respiratory parameters were determined using linear and nonlinear methods to analyze heart rate (HRV) and blood pressure variability (BPV). During the complete test, HRV was lower in healthy men than in female controls. Decreased HRV and increased BPV were observed in female patients compared to healthy women. Furthermore, systolic BPV was increased in male and female patients. However, linear (rmssd) and nonlinear (plvar2) parameters indicated that diastolic BPV decreased in male patients during orthostatic phase, but remained unchanged in female patients. Findings indicated gender dependent mechanisms for the regulation of diastolic blood pressure during orthostatic stress in patients.

Study of impaired cardiovascular and respiratory coupling during orthostatic stress based on joint symbolic dynamics.

The present study investigates the instantaneous coupling among the cardiac, vascular, and respiratory systems, using the heart rate, respiration, and systolic and diastolic blood pressure variability in 12 healthy and 16 vasovagal syncope female subjects during a head-up tilt (HUT) testing protocol at 70° This study contributes to the coupling analysis by using a nonlinear joint symbolic dynamics (JSD) in a high-temporal resolution scheme, based on 5 min segments of the time series that are shifted every minute. For each segment, a bivariate JSD matrix was constructed to obtain global and local coupling indices in accordance to Shannon's entropy and the probability of occurrence of various bivariate words, respectively. The novel approach revealed important findings in the coupling dynamics of the systems, thus allowing the detection of group differences during the early orthostatic phase, and during the HUT test, before the occurrence of any pre-syncopal symptoms. In patients, the global indices indicated a significant decrease of cardiovascular coupling, starting at 10 min after the tilt-up, manifested by reduced baroreflex sensitivity and cardiorespiratory coupling that was initiated 8 min after the onset of the orthostatic phase (OP). A decreased autonomic control on cardiovascular-respiratory couplings was further evidenced by increased alterations of the JSD indices during the OP compared to the supine position in patients compared to controls. Furthermore, findings based on local indices demonstrated that female patients showed reductions and disengagements in cardiovascular (p < 0.001) and cardiorespiratory (p < 0.01) couplings, as early as the first 5 min and during the complete OP.

Multivariate symbolic dynamics for analysis of respiratory-cardiovascular interactions.

In this work, a nonlinear method to study multivariate interactions, called multivariate symbolic dynamics (MSD), was introduced. The usefulness of this technique was studied on respiratory-cardiovascular data from young women with vasovagal syncope (VVS) and from healthy subjects. The study included 16 female patients diagnosed with VVS and 24 age-matched healthy subjects (12 women). All subjects were enrolled in a head-up tilt (HUT) test, breathing normally, including 5 min of supine position and 18 to 28 min of 70° orthostatic phase. The MSD parameters were dynamically obtained for 5-min windows shifted by 1 min during HUT test. In supine position there were no considerable differences. During orthostatic phase, parameters from MSD showed a highly significantly (p=0.00005) increased occurrence of impaired respiratory-cardiovascular interactions in female patients susceptible to vasovagal syncope. This study provided promising results for a new multivariate method to investigate respiratory-cardiovascular interactions.

Men and women should be separately investigated in studies of orthostatic challenge due to different gender-related dynamics of autonomic response.

In studies of autonomic regulation during orthostatic challenges only a few nonlinear methods have been considered without investigating the effect of gender in young controls. Especially, the temporal development of the autonomic regulation has not yet been explicitly analyzed using short-term segments in supine position, transition and orthostatic phase (OP). In this study, nonlinear analysis of cardiovascular and respiratory time series was performed to investigate how nonlinear indices are dynamically changing with respect to gender during orthostatic challenges. The analysis was carried out using shifted short-term segments throughout a head-up tilt test in 24 healthy subjects, 12 men (26 ± 4 years) and 12 age-matched women (26 ± 5 years), at supine position and during OP at 70°. The nonlinear methods demonstrated statistical differences in the autonomic regulation between males and females. Orthostatic stress caused significantly decreased heart rate variability due to increased sympathetic activity mainly in men, already at the beginning and during the complete OP, revealed by (a) increased occurrence of specific word types with constant fluctuations as pW111 from symbolic dynamics, (b) augmented fractal correlation properties by the short-term index alpha1 from detrended fluctuation analysis, (c) increased slope indices (21ati and 31ati) from auto-transinformation and (d) augmented time irreversibility indices demonstrating more temporal asymmetries and nonlinear dynamics in men than in women. After tilt-up, both men and women increased their sympathetic activity but in a different way. Time-dependent gender differences during orthostatic challenge were shown directly between men and women or indirectly comparing baseline and different temporal stages of OP. The proposed dynamical study of autonomic regulation has the advantage of screening the fluctuations of the sympathetic and vagal activities that can be quantified by the temporal behavior of nonlinear indices. The findings in this paper strongly suggest the need for gender separation in studies of the dynamics of autonomic regulation during orthostatic challenge.

Orthostatic stress causes immediately increased blood pressure variability in women with vasovagal syncope.

The cardiovascular and respiratory autonomic nervous regulation has been studied mainly by hemodynamic responses during different physical stressors. In this study, dynamics of autonomic response to an orthostatic challenge was investigated by hemodynamic variables and by diverse linear and nonlinear indices calculated from time series of beat-to-beat intervals (BBI), respiratory cycle duration (RESP), systolic (SYS) and diastolic (DIA) blood pressure. This study included 16 young female patients (SYN) with vasovagal syncope and 12 age-matched female controls (CON). The subjects were enrolled in a head-up tilt (HUT) test, breathing normally, including 5min of baseline (BL, supine position) and 18min of 70° orthostatic phase (OP). To increase the time resolution of the analysis the time series were segmented in five-minute overlapping windows with a shift of 1min. Hemodynamic parameters did not show any statistical differences between SYN and CON. Time domain linear analysis revealed increased respiratory frequency and increased blood pressure variability (BPV) in patients during OP meaning increased sympathetic activity and vagal withdrawal. Frequency domain analysis confirmed a predominance of sympathetic tone by steadily increased values of low over high frequency power in BBI and of low frequency power in SYS and DIA in patients during OP. The nonlinear analysis by symbolic dynamics seemed to be highly suitable for differentiation of SYN and CON in the early beginning of OP, i.e., 5min after tilt-up. In particular the index SYS_plvar3 showed less patterns of low variability in patients reflecting a steadily increase in both BPV and sympathetic activity. The proposed dynamical analysis could lead to a better understanding of the temporal underlying mechanisms in healthy subjects and patients under orthostatic stress.

Delta space plot analysis of cardiovascular coupling in vasovagal syncope during orthostatic challenge.

In this work, a graphical method to study cardiovascular coupling, called delta space plot analysis (DSPA), was introduced. The graphical representation is susceptible to be parameterized in shape and orientation. The usefulness of this technique was studied on cardiovascular data from patients with vasovagal syncope (VVS) and from controls. The study included 15 female patients diagnosed with VVS and 11 age-matched healthy female subjects. All subjects were enrolled in a head-up tilt (HUT) test, breathing normally, including 5 minutes of supine position (baseline) and 18 minutes of 70° orthostatic phase. The DSPA parameters were obtained at different times during the HUT test, i.e., at baseline, early (first 5 min) and late (10-15 min) orthostatic phases. In baseline there were no considerable differences between female controls and female patients. During the late orthostatic phase, parameters from DSPA showed highly significantly (p=0.000003) reduced cardiovascular coupling in patients. Findings indicated a loss of control on cardiovascular coupling in female patients susceptible to vasovagal syncope during orthostatic challenge. In addition, this study provided promising results for a new graphical method to investigate cardiovascular coupling.

Temporal analysis of cardiac autonomic regulation during orthostatic challenge by short-term symbolic dynamics.

The gradual shift of cardiac autonomic regulation toward sympathetic predominance and vagal withdrawal during graded head-up tilt test in young controls has been demonstrated by parameters from symbolic dynamics obtained from short-term heart rate variability (HRV) analysis. In this study, the influence of gender and vasovagal syncope (VVS) on the autonomic response to an orthostatic challenge was investigated by HRV analysis using short-term symbolic dynamics (STSD). This study included 24 healthy young subjects (12 males; 12 age-matched females) and 16 female patients diagnosed with VVS. All subjects were enrolled in a head-up tilt (HUT) test, breathing normally, including 5 minutes of supine position (baseline) and 20-40 minutes of 70° orthostatic phase. The STSD parameters were obtained following their behavior at different times during the HUT test, i.e., at baseline, early and middle orthostatic phases. Gender differences including increased sympathetic activity in men were already present in baseline and in the middle tilt phase. In baseline there were no differences between female controls and female patients, but parameters from STSD showed highly significantly (p=0.0007) reduced heart rate variability due to increased sympathetic activity in female patients in the middle tilt phase. Furthermore a new nonlinear index for the estimation of sympatho-vagal balance was introduced.

Gender differences in cardiovascular and cardiorespiratory coupling in healthy subjects during head-up tilt test by Joint Symbolic Dynamics.

Gender related-differences in the autonomic regulation of the cardiovascular and cardiorespiratory systems have been studied mainly by hemodynamic responses during different physical stressors. In this study, the influence of gender on the autonomic response to an orthostatic challenge was investigated by obtaining the cardiovascular and cardiorespiratory coupling using the nonlinear technique known as joint symbolic dynamics (JSD) representation. This study includes 24 healthy young subjects. Males (N=12) and age-matched females (N=12) were enrolled in a head-up tilt (HUT) test, breathing normally, including 5 minutes of supine position (baseline) and 25-40 minutes of 70° orthostatic phase. The cardiovascular and cardiorespiratory couplings were obtained at baseline, early and middle orthostatic phases. Although in baseline there were some gender differences, parameters from JSD showed highly significant (p=0.0004) differences in specific cardiovascular coupling patterns in the early tilt phase. Furthermore, JSD analysis revealed that in males, due to increased sympathetic activity, exist a lower degree of cardiovascular coupling accompanied with an increased occurrence of tachycardic patterns. On the other hand, the cardiorespiratory coupling revealed only very few slightly significant differences in all three phases.

Smelling heart failure from human skin odor with an electronic nose.

The human body odor contains different volatile organic compounds which can be used as biomarkers for various diseases. The early detection of heart failure (HF) through periodical screening provides an early treatment application. Therefore we have developed a completely new non-invasive method to identify HF applying an "electronic nose" (e-nose) which provides a "smelling" of the disease based on the analysis of sweat volatile gases from the skin surface. For this e-nose a special applicator carrying the sensor chip was developed which can be applied directly on the skin surface. 27 patients with decompensated HF (DHF), 25 patients with compensated HF (CHF, mean age 70.72 ± 12.02) and 28 controls (CON) were enrolled in this first pilot study.

Quantification of cardiovascular and cardiorespiratory coupling during hypoxia with Joint Symbolic Dynamics.

Newborn mammals suffering from moderate hypoxia during or after birth are able to compensate a transitory lack of oxygen by adaptation of their vital functions. However, limited information is available about bivariate couplings of the underlying complex processes controlled by the autonomic nervous system. In this study an animal model of seven newborn piglets (2-3 days old, 1.71 ± 0.15 kg) was used. The aim of this study was to analyze the cardiovascular and cardiorespiratory interactions of autonomous nervous system during sustained hypoxia and the interrelationship of these autonomic time series after induced reoxygenation. For this purpose we applied a new high resolution version of the nonlinear method of Joint Symbolic Dynamics (JSD) for analysis of couplings between heart rate and blood pressure and respiration rate time series, respectively. This new method is characterized by using three defined symbols (JSD3) instead of two and the application of thresholds for the symbol transformation. Our results demonstrate that in contrast to the traditional JSD the comparison of cardiovascular interactions reveals only significant differences between normoxic and hypoxic conditions using JSD3 whereas for cardiorespiratory interactions significant differences were revealed by indices from both JSD2 and JSD3 due to reoxygenation. These results suggest that the application of JSD3 reveals more detailed information about cardiovascular and cardiorespiratory interactions of autonomic regulation and might be useful for monitoring of critical human newborns.