Phenotyping congestion in patients with acutely decompensated heart failure with preserved and reduced ejection fraction: The Decongestion duRing therapY for acute decOmpensated heart failure in HFpEF vs HFrEF- DRY-OFF study.

AIMS: To evaluate pulmonary and intravascular congestion at admission and repeatedly during hospitalization for acute decompensated heart failure (ADHF) in HFrEF and HFpEF patients using lung (LUS) and inferior vena cava (IVC) ultrasound. METHODS AND RESULTS: Three-hundred-fourteen patients (82±9 years; HFpEF =172; HFrEF=142) admitted to Internal Medicine wards for ADHF were enrolled in a multi-center prospective study. At admission HFrEF presented higher indexes of pulmonary and intravascular congestion (LUS-score: 0.9 ±â€¯0.4 vs 0.7 ±â€¯0.4; p<0.01; IVC end-expiratory diameter: 21.6 ±â€¯5.1 mm vs 20±5.5 mm, p<0.01; IVC collapsibility index 24.4 ±â€¯17.4% vs 30.9 ±â€¯21.1% p<0.01) and higher Nt-proBNP values (8010 vs 3900 ng/l; p<0.001). At discharge, HFrEF still presented higher B-scores (0.4 ±â€¯4 vs 0.3 ±â€¯0.4; p = 0.023), while intravascular congestion improved to a greater extent, thus IVC measurements were similar in the two groups. No differences in diuretic doses, urine output, hemoconcentration, worsening renal function were found. At 90-days follow up HF readmission/death did not differ in HFpEF and HFrEF (28% vs 31%, p = 0,48). Residual congestion was associated with HF readmission/death considering the whole population; while intravascular congestion predicted readmission/death in the HFrEF, no association between sonographic indexes and the outcome was found in HFpEF. CONCLUSIONS: Serial assessment of pulmonary and intravascular congestion revealed a higher burden of fluid overload in HFrEF and, conversely, a greater reduction in intravascular venous congestion with diuretic treatment. Although other factors beyond EF could play a role in congestion/decongestion patterns, our data may be relevant for further phenotyping HF patients, considering the importance of decongestion optimization in the clinical approach.

Hypoalbuminemia in COVID-19: assessing the hypothesis for underlying pulmonary capillary leakage.

BACKGROUND: Since the first observations of patients with COVID-19, significant hypoalbuminaemia was detected. Its causes have not been investigated yet. OBJECTIVE: We hypothesized that pulmonary capillary leakage affects the severity of respiratory failure, causing a shift of fluids and proteins through the epithelial-endothelial barrier. METHODS: One hundred seventy-four COVID-19 patients with respiratory symptoms, 92 admitted to the intermediate medicine ward (IMW) and 82 to the intensive care unit (ICU) at Luigi Sacco Hospital in Milan, were studied. RESULTS: Baseline characteristics at admission were considered. Proteins, interleukin 8 (IL-8) and interleukin 10 (IL-10) in bronchoalveolar lavage fluid (BALF) were analysed in 26 ICU patients. In addition, ten autopsy ultrastructural lung studies were performed in patients with COVID-19 and compared with postmortem findings in a control group (bacterial pneumonia-ARDS and H1N1-ARDS). ICU patients had lower serum albumin than IMW patients [20 (18-23) vs 28 (24-33) g L-1 , P < 0.001]. Serum albumin was lower in more compromised groups (lower PaO2 -to-FiO2 ratio and worst chest X-ray findings) and was associated with 30 days of probability of survival. Protein concentration was correlated with IL-8 and IL-10 levels in BALF. Electron microscopy examinations of eight out of ten COVID-19 lung tissues showed loosening of junctional complexes, quantitatively more pronounced than in controls, and direct viral infection of type 2 pneumocytes and endothelial cells. CONCLUSION: Hypoalbuminaemia may serve as severity marker of epithelial-endothelial damage in patients with COVID-19. There are clues that pulmonary capillary leak syndrome plays a key role in the pathogenesis of COVID-19 and might be a potential therapeutic target.

Residual congestion and long-term prognosis in acutely decompensated heart failure patients.

AIMS: Recent studies have established the role of residual congestion evaluated by lung ultrasound in estimating short-term risk of readmission or death in patients admitted for heart failure (HF) decompensation. However, if lung ultrasounds maintain a prognostic role of in long-term survival is still unknown. Aim of our study was to evaluate if residual congestion could predict all-cause mortality during 4 year follow up in a cohort of unselected patients admitted for acute decompensated HF. METHODS: One-hundred fifty patients were enrolled. The anterolateral chest was scanned to evaluate the presence of B-lines. A sonographic score was calculated attributing 1 to each positive sector (≥ 3 B-lines). Clinical, biochemical and echocardiographic data were recorded. A Cox proportional hazard regression analysis was performed to evaluate the association between variables and 4-year survival. RESULTS: During the follow-up, 86 patients (58%) died. Univariate analysis showed a significant correlation between the sonographic score at discharge and events occurrence at long term follow up (HR 1.21; CI 1.11-1.31; p < 0.001) suggesting that, on average, the increase of 1 point in the sonographic score was associated with an increase of approximately 20% in the risk of death. CONCLUSIONS: Our results suggest the role of LUS in the identification of more congested HF patients, that will be at risk for worse long term outcome.

Point-of-care ultrasound in internal medicine: A position paper by the ultrasound working group of the European federation of internal medicine.

Point-of-care ultrasound (POCUS) is increasingly used to assess medical patients. It has many uses in daily clinical practice, including improved diagnostic timeliness and accuracy, and providing information about a patient's prognosis and follow-up. It has been integrated into numerous specialities, but remains relatively undefined in internal medicine training programs. Ultrasonography is a useful tool in the standard clinical practice of internists in numerous clinical scenarios (Emergency Department, hospital ward, general and specific consultations, and home care). Although POCUS has been recently included in the European curriculum of internal medicine, there are differences between European internists in its use, ranging from not at all to well structured educational programs. The use of POCUS needs to be widespread in internal medicine departments, and to accomplish this we must encourage structured training. This document details the consensus-based recommendations by the European Federation of Internal Medicine (EFIM) Ultrasound working group. We establish POCUS core competencies and clinical settings for internists in a symptom-based approach. We also propose training requirements, providing a framework for training programs at a national level.

Lung ultrasonography in pulmonary tuberculosis: A pilot study on diagnostic accuracy in a high-risk population.

OBJECTIVES: The validity of lung ultrasound (LUS) in the diagnosis of interstitial or focal lung pathologies is well documented, we assessed its accuracy in the diagnosis of pulmonary tuberculosis (PTB). METHODS: Sonographic signs suggestive of PTB and their diagnostic accuracy were evaluated in patients admitted with clinical suspicion of PTB. Consolidations, subpleural nodules, pleural thickenings or irregularities and pleural effusion were assessed. LUS signs significantly associated with PTB in the univariate analysis (p < .05) were entered in a multivariate logistic regression model. RESULTS: PTB was confirmed in 51 out of 102 patients. Multiple consolidations (OR 3.54, 95%CI 1.43-8.78), apical consolidations (OR 9.65, 95%CI 3.02-30.78), superior quadrant consolidations (OR 4.01, 95%CI 1.76-9.14), and subpleural nodules (OR 5.29, 95%CI 2.27-12.33) were significantly associated with PTB diagnosis. Apical consolidation (OR 9.67, 95%CI 2.81-33.25, p 0.003) and subpleural nodules (OR 5.30, 95%CI 2.08-13.52, p 0.005) retained a significant association in a multivariate model, with an overall accuracy of 0.799. CONCLUSIONS: Our data suggest a possible role of LUS in the diagnosis of PTB, a high burden pathological condition for which the delay in diagnosis still represents a critical point in the control of the disease.

Chagas disease knocks on our door: a cross-sectional study among Latin American immigrants in Milan, Italy.

OBJECTIVES: We aimed to assess the prevalence and risk factors for Chagas disease (CD) in Latin American immigrants and to evaluate the accuracy of diagnostic tests. Moreover, we offered to all positive subjects a complete free-of-charge clinical/instrumental evaluation as well as benznidazole treatment in order to stage the disease and verify drug tolerability. METHODS: A cross-sectional survey of CD among Latin Americans living in Milan and its metropolitan area was conducted between July 2013 and July 2014. Blood samples were tested for serologic evidence of CD together with a questionnaire covering demographic and clinical-epidemiological information. RESULTS: Forty-eight (9.6%) of the 501 tested subjects were conclusively diagnosed as having CD. The highest prevalence of CD was among those from Bolivia (43/169, 25.4%) and El Salvador (4/68, 5.9%). Older age (adjusted odds ratio (aOR)] 1.05, p =0.004), a Bolivian origin (aOR 8.80; p =0.003), being born in the department of Santa Cruz (aOR 3.72, p =0.047), having lived in mud houses (aOR 2.68; p =0.019), and having an affected relative (aOR 12.77, p =0.001) were independently associated with CD. The ARCHITECT Chagas test showed the highest sensitivity (100%) and specificity (99.8%). Twenty-nine of the subjects with CD (60.4%) underwent disease staging, 10 of whom (35.7%) showed cardiac and/or digestive involvement. Benznidazole treatment was associated with high frequency of adverse reactions (19/27, 70.4%) and permanent discontinuation (8/27, 29.6%). CONCLUSIONS: CD is highly prevalent among Bolivians and Salvadorans living in Milan. Regions with a large Latin American immigrant population should implement programmes of active detection and treatment.

Automatic classification of interference patterns in driven event series: application to single sympathetic neuron discharge forced by mechanical ventilation.

This study proposes a method for the automatic classification of nonlinear interactions between a strictly periodical event series modelling the activity of an exogenous oscillator working at a fixed and well-known rate and an event series modelling the activity of a self-sustained oscillator forced by the exogenous one. The method is based on a combination of several well-known tools (probability density function of the cyclic relative phase, probability density function of the count of forced events per forcing cycle, conditional entropy of the cyclic relative phase sequence and a surrogate data approach). Classification is reached via a sequence of easily applicable decision rules, thus rendering classification virtually user-independent and fully reproducible. The method classifies four types of dynamics: full uncoupling, quasiperiodicity, phase locking and aperiodicity. In the case of phase locking, the coupling ratio (i.e. n: m) and the strength of the coupling are calculated. The method, validated on simulations of simple and complex phase-locking dynamics corrupted by different levels of noise, is applied to data derived from one anesthetized and artificially ventilated rat to classify the nonlinear interactions between mechanical ventilation and: (1) the discharges of two (contemporaneously recorded) single postganglionic sympathetic neurons innervating the caudal ventral artery in the tail and (2) arterial blood pressure. Under central apnea, the activity of the underlying sympathetic oscillators is perturbed by means of five different lung inflation rates (0.58, 0.64, 0.76, 0.95, 1.99 Hz). While ventilation and arterial pressure are fully uncoupled, ventilation is capable of phase locking sympathetic discharges, thus producing 40% of phase-locked patterns (one case of 2:5, 1:1, 3:2 and 2:2) and 40% of aperiodic dynamics. In the case of phase-locked patterns, the coupling strength is low, thus demonstrating that this pattern is sliding. Non-stationary interactions are observed in 20% of cases. The two discharges behave differently, suggesting the presence of a population of sympathetic oscillators working at different frequencies.

Sympathetic rhythms and cardiovascular oscillations.

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.

[Spectral analysis of muscle sympathetic nerve activity in man]. / Analisi spettrale dell'attività nervosa simpatica muscolare nell'uomo.

Recent applications of frequency domain analysis to the variability of muscle sympathetic nerve activity (MSNA) have improved the comprehension of the relationship between cardiovascular oscillations and the autonomic nervous system. It has been observed that spectral analysis of MSNA is characterized by two major oscillatory components at low (LF) and high (HF) frequencies, similar to those detectable in the variability of cardiovascular signals. Pharmacological and non-pharmacological studies have shown that, at least within the physiological range, the two MSNA rhythms show a reciprocal behavior, similar to that already observed for cardiovascular oscillations. The oscillatory pattern of MSNA provides non-redundant but complementary information with respect to the time domain measures of MSNA (burst rate and amplitude) since it has been shown that completely different spectral profiles may be derived from various MSNA recordings. On the other hand, the latter are instead comparable in terms of mass activity. Due to the intrinsic characteristics of the signal, which represents the direct outflow of the central neural structures of the cardiovascular autonomic nervous system, this approach can be considered as a unique window over the central organization of excitatory and inhibitory neural mechanisms responsible for the genesis and the regulation of cardiovascular oscillations.

Comparison of low-dose dobutamine ventriculography with low-dose dobutamine echocardiography for predicting regional improvement in left ventricular function after coronary artery bypass grafting.

The demonstration of a contractile reserve during low-dose dobutamine echocardiography (LDDE) identifies viable myocardium and predicts recovery of left ventricular (LV) function after myocardial revascularization in patients with chronic coronary artery disease. However, a technically difficult transthoracic visualization may limit the use of LDDE, thus requiring an alternative diagnostic procedure. The present study compares LDDE with low-dose dobutamine ventriculography (LDDV) in predicting an improvement in regional LV function after surgical revascularization. We studied 18 patients with coronary artery disease and LV dysfunction who were to undergo coronary artery bypass grafting. Preoperatively, all patients were evaluated for the presence of viable myocardium using LDDE and LDDV. Follow-up echocardiography at rest and left ventriculography were performed 4 months after successful revascularization to assess recovery of LV function. The sensitivity and specificity of LDDE to identify dysfunctional segments capable of recovering function were 63% and 71%, respectively, with a diagnostic accuracy of 68%. The sensitivity, specificity, and diagnostic accuracy of LDDE improved to 81%, 72%, and 76% when patients with optimal transthoracic evaluation were selected, whereas they were 30%, 77%, and 57%, respectively, in those who underwent suboptimal evaluation. The sensitivity, specificity, and diagnostic accuracy of LDDV were 66%, 75%, and 71%, respectively, with no difference in subgroups of patients. This study demonstrates that LDDV can be considered a useful technique for identifying the presence of myocardial viability and may provide an advantage over LDDE in patients with suboptimal echocardiographic visualization.

Detection of low- and high-frequency rhythms in the variability of skin sympathetic nerve activity.

Spectral analysis of skin blood flow has demonstrated low-frequency (LF, 0.03-0.15 Hz) and high-frequency (HF, 0.15-0.40 Hz) oscillations, similar to oscillations in R-R interval, systolic pressure, and muscle sympathetic nerve activity (MSNA). It is not known whether the oscillatory profile of skin blood flow is secondary to oscillations in arterial pressure or to oscillations in skin sympathetic nerve activity (SSNA). MSNA and SSNA differ markedly with regard to control mechanisms and morphology. MSNA contains vasoconstrictor fibers directed to muscle vasculature, closely regulated by baroreceptors. SSNA contains both vasomotor and sudomotor fibers, differentially responding to arousals and thermal stimuli. Nevertheless, MSNA and SSNA share certain common characteristics. We tested the hypothesis that LF and HF oscillatory components are evident in SSNA, similar to the oscillatory components present in MSNA. We studied 18 healthy normal subjects and obtained sequential measurements of MSNA and SSNA from the peroneal nerve during supine rest. Measurements were also obtained of the electrocardiogram, beat-by-beat blood pressure (Finapres), and respiration. Spectral analysis showed LF and HF oscillations in MSNA, coherent with similar oscillations in both R-R interval and systolic pressure. The HF oscillation of MSNA was coherent with respiration. Similarly, LF and HF spectral components were evident in SSNA variability, coherent with corresponding variability components of R-R interval and systolic pressure. HF oscillations of SSNA were coherent with respiration. Thus our data suggest that these oscillations may be fundamental characteristics shared by MSNA and SSNA, possibly reflecting common central mechanisms regulating sympathetic outflows subserving different regions and functions.

Effects of spinal section and of positive-feedback excitatory reflex on sympathetic and heart rate variability.

The sympathetic outflow appears to be capable of displaying a rhythmicity synchronous with cardiovascular Mayer's waves even after spinal section. To test the hypothesis that spinal sympathetic low frequency (LF) oscillation can be enhanced during sympathetic excitation, we recorded cardiac sympathetic nerve activity (SNA), R-R interval, arterial pressure, and ventilation in 9 unanesthetized decerebrate-vagotomized cats before and after C1 spinal section. LF and high frequency (HF) components were detected in the variability of SNA, R-R interval, and systolic arterial pressure both before and after spinal section. In this latter condition, a significant coherence between LF(SNA) and LF(R-R) was present in 5 animals, whereas HF(SNA) and HF(R-R) were correlated in 4 animals. During an excitatory sympathetic spinal reflex elicited by aortic constriction, the efferent sympathetic firing was markedly enhanced (from 7+/-2 to 33+/-7 spikes/s); concomitantly, the powers of both LF(SNA) and HF(SNA) were also increased. Coherence between LF(SNA) and LF(R-R) became significant in all cases, whereas HF(SNA) and HF(R-R) became correlated in 6 animals. In 3 animals, the reflex sympathetic excitation was no longer elicitable after interrupting a vast contingent of sympathetic afferents by means of thoracic dorsal root section. We report for the first time that LF and HF oscillations are detectable in SNA, R-R interval, and systolic arterial pressure variabilities of decerebrate-vagotomized spinal cats and that an excitatory spinal reflex is capable of increasing the power of both SNA spectral components.

Myocardial beta-adrenergic and muscarinic receptor density in cardiac pressure or volume overload.

Decreased myocardial beta-adrenergic receptor density has been demonstrated in experimental and clinical models of cardiac disease. Nevertheless, the individual role played by pressure or volume overload in determining the receptor downregulation has never been described in humans. Moreover, no data have been reported about the reversibility of the downregulation after non-pharmacological improvement of cardiac function. In the present study, we measured the myocardial beta-adrenergic and muscarinic receptor density, using an autoradiographic method, in 14 patients with cardiac pressure overload (aortic stenosis) and in five patients with cardiac volume overload (aortic regurgitation). Five patients with aortic stenosis were studied again six months after successful valve replacement. A significant lower density of beta-adrenergic receptors was observed in patients with a chronic pressure overload compared to those with a chronic volume overload (20+/-2 and 28+/-2 fmol/mg protein, respectively P<0.05). No significant differences were found between the two groups regarding beta-adrenoceptor sub-types proportion and muscarinic receptor density. Six months after successful aortic valve replacement, we observed a significant upregulation of the beta-adrenoceptor density (delta 29+/-9 fmol/mg protein P<0.05). In conclusion, these observations indicate that: (a) the type of left ventricle haemodynamic overload may be a quantitative determinant factor in the myocardial beta-adrenoceptor downregulation; (b) the reduction of a pathological cardiac load leads to an upregulation of these receptors.

Central vagotonic effects of atropine modulate spectral oscillations of sympathetic nerve activity.

BACKGROUND: Low-dose atropine causes bradycardia either by acting on the sinoatrial node or by its effects on central muscarinic receptors increasing vagal activity. Any central muscarinic effects of high-dose atropine on RR interval are masked by peripheral muscarinic blockade at the sinoatrial node, which causes tachycardia. Effects of central parasympathetic activation on sympathetic activity are not known. METHODS AND RESULTS: Using power spectral analysis of RR interval, intra-arterial blood pressure, respiration, and muscle sympathetic nerve activity (MSNA), we examined the effects of both low (2 microgram/kg IV) and high (15 microgram/kg IV) doses of atropine. After low-dose atropine, RR increased by 9+/-1% (P<0.0001), the low-frequency (LF) component (in normalized units, NU) of RR variability decreased by -32+/-8%, and the high-frequency (HF)NU component increased (+74+/-19%); hence, LF/HF of RR variability fell by 52+/-10% (all P<0.01). Although overall MSNA did not change, LFNU of MSNA decreased (-15+/-5%), HFNU of MSNA increased (+31+/-3%), and LF/HF of MSNA fell (-41+/-8%) (all P<0.01). After high-dose atropine, LFNU of MSNA decreased (-17+/-12%), HFNU of MSNA increased (+22+/-3%), and LF/HF of MSNA fell (-51+/-21%) (all P<0.02). CONCLUSIONS: Increasing central parasympathetic activity with low-dose atropine is associated with an increase in the HF and a decrease in the LF oscillations of both RR interval and MSNA variability. High-dose atropine similarly induces an increase in the HF and a decrease in the LF components of MSNA variability. Thus, central parasympathetic activation is able to modulate the oscillatory characteristics of sympathetic nerve traffic to peripheral blood vessels.

Altered cardiovascular variability in obstructive sleep apnea.

BACKGROUND: Altered cardiovascular variability is a prognostic indicator for cardiovascular events. Patients with obstructive sleep apnea (OSA) are at an increased risk for cardiovascular disease. We tested the hypothesis that OSA is accompanied by alterations in cardiovascular variability, even in the absence of overt cardiovascular disease. METHODS AND RESULTS: Spectral analysis of variability of muscle sympathetic nerve activity, RR interval, and blood pressure were obtained during undisturbed supine rest in 15 patients with moderate-to-severe OSA, 18 patients with mild OSA, and 16 healthy control subjects in whom sleep disordered breathing was excluded by complete overnight polysomnography. Patients with OSA were newly diagnosed, never treated for OSA, and free of any other known diseases. Patients with moderate-to-severe OSA had shorter RR intervals (793+/-27 ms) and increased sympathetic burst frequency (49+/-4 bursts/min) compared with control subjects (947+/-42 ms; 24+/-3 bursts/min; P=0.008 and P<0.001, respectively). In these patients, total variance of RR was reduced (P=0.01) and spectral analysis of RR variability showed an increase in low frequency normalized units, a decrease in high frequency normalized units, and an increase in the ratio of low to high frequency (all P<0.05). Even though blood pressure was similar to that of the control subjects, blood pressure variance in patients with moderate-to-severe OSA was more than double the variance in control subjects (P=0.01). Patients with mild OSA also had a reduction in RR variance (P=0.02) in the absence of any significant difference in absolute RR interval. For all patients with OSA, linear regression showed a positive correlation (r=0.40; P=0.02) between sleep apnea severity and blood pressure variance. CONCLUSIONS: Cardiovascular variability is altered in patients with OSA. This alteration is evident even in the absence of hypertension, heart failure, or other disease states and may be linked to the severity of OSA. Abnormalities in cardiovascular variability may be implicated in the subsequent development of overt cardiovascular disease in patients with OSA.

Evidence for a central origin of the low-frequency oscillation in RR-interval variability.

BACKGROUND: Short-term variability of RR interval and blood pressure occurs predominantly at low frequency (LF; approximately 0.1 Hz) and high frequency (approximately 0.25 Hz). The arterial baroreflex is thought to be the predominant determinant of the LF component of RR variability. Patients with severe congestive heart failure (CHF) have an attenuated or absent LF oscillation in RR variability. The left ventricular assist device (LVAD) offers a unique possibility for analysis of spectral oscillations in RR interval independent of any effects of blood pressure that influence these oscillations via the baroreflex. METHODS AND RESULTS: We performed spectral analysis of RR, blood pressure, and respiration in 2 patients with CHF before and after LVAD implantation. LF components of the RR-interval and blood pressure variability were absent in both CHF patients before LVAD implantation. After LVAD implantation, spectral analysis of the RR interval showed restoration of a clear and predominant LF oscillation in the native hearts of both patients, with no such oscillation evident in the blood pressure profile. CONCLUSIONS: During total circulatory support with the LVAD, the LF oscillation in RR interval of the native heart, absent in CHF, is restored. This LF oscillation in RR interval occurs in the absence of LF oscillations in blood pressure and thus is unlikely to be explained by baroreflex mechanisms. Hence, the absence of LF oscillation in the RR interval in CHF is functional and is reversible by LVAD circulation. The presence of a predominant LF oscillation in RR interval independent of any oscillation in blood pressure suggests that the LF oscillation is a fundamental property of central autonomic outflow.

Measuring regularity by means of a corrected conditional entropy in sympathetic outflow.

A new method for measuring the regularity of a process over short data sequences is reported. This method is based on the definition of a new function (the corrected conditional entropy) and on the extraction of its minimum. This value is taken as an index in the information domain quantifying the regularity of the process. The corrected conditional entropy is designed to decrease in relation to the regularity of the process (like other estimates of the entropy rate), but it is able to increase when no robust statistic can be performed as a result of a limited amount of available samples. As a consequence of the minimisation procedure, the proposed index is obtained without an a-priori definition of the pattern length (i.e. of the embedding dimension of the reconstructed phase space). The method is validated on simulations and applied to beat-to-beat sequences of the sympathetic discharge obtained from decerebrate artificially ventilated cats. At control, regular, both quasiperiodic and periodic (locked to ventilation) dynamics are observed. During the sympathetic activation induced by inferior vena cava occlusion, the presence of phase-locked patterns and the increase in regularity of the sympathetic discharge evidence an augmented coupling between the sympathetic discharge and ventilation. The reduction of complexity of the neural control obtained by spinalization decreases the regularity in the sympathetic outflow, thus pointing to a weaker coupling between the sympathetic discharge and ventilation.

Non-linear dynamics and chaotic indices in heart rate variability of normal subjects and heart-transplanted patients.

OBJECTIVES: Heart rate variability (HRV) is characterised by a variety of linear, non-linear, periodical and non-periodical oscillations. The aim of the present study was mainly to investigate the role played by neural mechanisms in determining non-linear and non-periodical components. METHODS: Analysis was performed in 7 recently heart transplanted patients and in 7 controls of similar age whose HRV signal was collected during 24 h. Parameters that quantify non-linear dynamic behaviour, in a time series, were calculated. We first assessed the specific non-linear nature of the time series by a test on surrogate data after Fourier phase randomization. Furthermore, the D2 correlation dimension, K2 Kolmogorov entropy, and H self-similarity exponent of the signal were estimated. From this last parameter, the dimension D = 1/H can be obtained. In order to assess whether the dynamics of the system are compatible with chaotic characteristics, the entire spectrum of Lyapunov exponents was calculated. We used return maps to graphically represent the non-linear and non-periodical behaviours in patients and controls. RESULTS: Surrogate data suggest that the HRV time courses have unique non-linear characteristics. D2, K2 and 1/H parameters were significantly lower in transplanted subjects than in controls. Positivity of the first Lyapunov exponent indicates divergence of trajectories in state-space. Furthermore, the display of return maps on projections obtained after Singular Value Decomposition, especially in low-complexity data (as in transplanted patients), shows a structure which is suggestive of a strange attractor. These findings support the hypothesis that chaotic dynamics underlie HRV. CONCLUSION: These results indicate that non-linear dynamics are likely to be present in HRV control mechanisms, giving rise to complex and qualitatively different behaviours. System complexity decreases in transplanted patients and this may be related to loss of the neural modulation of heart rate.