Publications

2024

1. Obstructive sleep apnea heterogeneity and autonomic function: a role for heart rate variability in therapy selection and efficacy monitoring.

   Hua Qin, Ingo Fietze, Diego R. Mazzotti, and 7 more authors

   Journal of sleep research, Feb 2024

   Place: England

   Abs Link

   Obstructive sleep apnea is a highly prevalent sleep-related breathing disorder, resulting in a disturbed breathing pattern, changes in blood gases, abnormal autonomic regulation, metabolic fluctuation, poor neurocognitive performance, and increased cardiovascular risk. With broad inter-individual differences recognised in risk factors, clinical symptoms, gene expression, physiological characteristics, and health outcomes, various obstructive sleep apnea subtypes have been identified. Therapeutic efficacy and its impact on outcomes, particularly for cardiovascular consequences, may also vary depending on these features in obstructive sleep apnea. A number of interventions such as positive airway pressure therapies, oral appliance, surgical treatment, and pharmaceutical options are available in clinical practice. Selecting an effective obstructive sleep apnea treatment and therapy is a challenging medical decision due to obstructive sleep apnea heterogeneity and numerous treatment modalities. Thus, an objective marker for clinical evaluation is warranted to estimate the treatment response in patients with obstructive sleep apnea. Currently, while the Apnea-Hypopnea Index is used for severity assessment of obstructive sleep apnea and still considered a major guide to diagnosis and managements of obstructive sleep apnea, the Apnea-Hypopnea Index is not a robust marker of symptoms, function, or outcome improvement. Abnormal cardiac autonomic modulation can provide additional insight to better understand obstructive sleep apnea phenotyping. Heart rate variability is a reliable neurocardiac tool to assess altered autonomic function and can also provide cardiovascular information in obstructive sleep apnea. Beyond the Apnea-Hypopnea Index, this review aims to discuss the role of heart rate variability as an indicator and predictor of therapeutic efficacy to different modalities in order to optimise tailored treatment for obstructive sleep apnea.

2023

1. Pathological Heart Rate Regulation in Apparently Healthy Individuals.

   Ludmila Sidorenko, Irina Sidorenko, Andrej Gapelyuk, and 1 more author

   Entropy (Basel, Switzerland), Jul 2023

   Place: Switzerland

   Abs Link

   Cardiovascular diseases are the leading cause of morbidity and mortality in adults worldwide. There is one common pathophysiological aspect present in all cardiovascular diseases-dysfunctional heart rhythm regulation. Taking this aspect into consideration for cardiovascular risk predictions opens important research perspectives, allowing for the development of preventive treatment techniques. The aim of this study was to find out whether certain pathologically appearing signs in the heart rate variability (HRV) of an apparently healthy person, even with high HRV, can be defined as biomarkers for a disturbed cardiac regulation and whether this can be treated preventively by a drug-free method. This multi-phase study included 218 healthy subjects of either sex, who consecutively visited the physician at Gesundheit clinic because of arterial hypertension, depression, headache, psycho-emotional stress, extreme weakness, disturbed night sleep, heart palpitations, or chest pain. In study phase A, baseline measurement to identify individuals with cardiovascular risks was done. Therefore, standard HRV, as well as the new cardiorhythmogram (CRG) method, were applied to all subjects. The new CRG analysis used here is based on the recently introduced LF drops and HF counter-regulation. Regarding the mechanisms of why these appear in a steady-state cardiorhythmmogram, they represent non-linear event-based dynamical HRV biomarkers. The next phase of the study, phase B, tested whether the pathologically appearing signs identified via CRG in phase A could be clinically influenced by drug-free treatment. In order to validate the new CRG method, it was supported by non-linear HRV analysis in both phase A and in phase B. Out of 218 subjects, the pathologically appearing signs could be detected in 130 cases (60%), p \textless 0.01, by the new CRG method, and by the standard HRV analysis in 40 cases (18%), p \textless 0.05. Thus, the CRG method was able to detect 42% more cases with pathologically appearing cardiac regulation. In addition, the comparative CRG analysis before and after treatment showed that the pathologically appearing signs could be clinically influenced without the use of medication. After treatment, the risk group decreased eight-fold-from 130 people to 16 (p \textless 0.01). Therefore, progression of the detected pathological signs to structural cardiac pathology or arrhythmia could be prevented in most of the cases. However, in the remaining risk group of 16 apparently healthy subjects, 8 people died due to all-cause mortality. In contrast, no other subject in this study has died so far. The non-linear parameter which is able to quantify the changes in CRGs before versus after treatment is FWRENYI4 (symbolic dynamic feature); it decreased from 2.85 to 2.53 (p \textless 0.001). In summary, signs of pathological cardiac regulation can be identified by the CRG analysis of apparently healthy subjects in the early stages of development of cardiac pathology. Thus, our method offers a sensitive biomarker for cardiovascular risks. The latter can be influenced by non-drug treatments (acupuncture) to stop the progression into structural cardiac pathologies or arrhythmias in most but not all of the patients. Therefore, this could be a real and easy-to-use supplemental method, contributing to primary prevention in cardiology.

2. Magnetocardiography at rest predicts cardiac death in patients with acute chest pain.

   N. Wessel, J. S. Kim, B. Y. Joung, and 7 more authors

   Frontiers in cardiovascular medicine, Jul 2023

   Place: Switzerland

   Abs Link

   INTRODUCTION: Sudden cardiac arrest is a major cause of morbidity and mortality worldwide and remains a major public health problem for which better non-invasive prediction tools are needed. Primary preventive therapies, such as implantable cardioverter defibrillators, are not personalized and not predictive. Most of these devices do not deliver life-saving therapy during their lifetime. The individual relationship between fatal arrhythmias and cardiac function abnormalities in predicting cardiac death risk has rarely been explored. METHODS: We retrospectively analyzed the measurements at rest for 191 patients with acute chest pain (ACP) magnetocardiographically. Our recently introduced analyses are able to detect inhomogeneities of the depolarization and repolarization. Moreover, electrically silent phenomena-intracellular ionic currents as well as vortex currents-can be measured and quantified. All included ACP patients were recruited in 2009 at Yonsei University Hospital and were followed up until 2022. RESULTS: During half of the follow-up period (6.5 years), 11 patients died. Out of all the included nine clinical, eight magnetocardiographical, and nine newly introduced magnetoionographical parameters we tested in this study, three parameters revealed themselves to be outstanding at predicting death: heart rate-corrected QT (QTc) prolongation, depression of repolarization current I(Kr) + I(Ks), and serum creatinine (all significant in Cox regression, p \textless 0.05). They clearly predicted cardiac death over the 6.5 years duration (sensitivity 90.9%, specificity 85.6%, negative predictive accuracy 99.4%). Cardiac death risk was more than ninefold higher in patients with low repolarization reserve and QTc prolongation in comparison with the remaining patients with ACP (p \textless 0.001). The non-parametric Kaplan-Meier statistics estimated significantly lower survival functions from their lifetime data (p \textless 0.001). DISCUSSION: To the best of our knowledge, these are the first data linking magnetocardiographical and magnetoionographical parameters and subsequent significant fatal events in people, suggesting structural and functional components to clinical life-threatening ventricular arrhythmogenesis. The findings support investigation of new prevention strategies and herald those new non-invasive techniques as complementary risk stratification tools.

3. Cardiac magnetic field map topology quantified by Kullback-Leibler entropy identifies patients with clinically suspected myocarditis.

   M. Pille, A. Gapelyuk, K. Berg, and 5 more authors

   Frontiers in cardiovascular medicine, Jul 2023

   Place: Switzerland

   Abs Link

   BACKGROUND: Myocarditis is a condition that can have severe adverse outcomes and lead to sudden cardiac death if remaining undetected. This study tested the capability of cardiac magnetic field mapping to detect patients with clinically suspected myocarditis. This could open up the way for rapid, non-invasive, and cost-effective screening of suspected cases before a gold standard assessment via endomyocardial biopsy. METHODS: Historical cardiac magnetic field maps (n = 97) and data from a state-of-the-art magnetocardiography device (n = 30) were analyzed using the Kullback-Leibler entropy (KLE) for dimensionality reduction and topological quantification. Linear discriminant analysis was used to discern between patients with ongoing myocarditis and healthy controls. RESULTS: The STT segment of a magnetocardiogram, i.e., the section between the end of the S wave and the end of the T wave, was best suited to discern both groups. Using a 250-ms excerpt from the onset of the STT segment gave a reliable classification between the myocarditis and control group for both historic data (sensitivity: 0.83, specificity: 0.85, accuracy: 0.84) and recent data (sensitivity: 0.69, specificity: 0.88, accuracy: 0.80) using the KLE to quantify the topology of the cardiac magnetic field map. CONCLUSION: The implementation based on KLE can reliably distinguish between clinically suspected myocarditis patients and healthy controls. We implemented an automatized feature selection based on LDA to replace the observer-dependent manual thresholding in previous studies.

4. REACT DX registry: Real world REACTion to atrial high rate episodes detected in implantable cardioverter-defibrillator recipients with a DX lead.

   Matthew O’Connor, Christof Kolb, Norbert Klein, and 12 more authors

   Technology and health care : official journal of the European Society for Engineering and Medicine, Jul 2023

   Place: Netherlands

   Abs Link

   BACKGROUND: Atrial fibrillation (AF) is associated with significant morbidity and is predicted by atrial high rate events. The early detection of AF is paramount to timely interventions to reduce the morbidity of AF. The DX ICD system combined with Home Monitoring® allows for continuous atrial rhythm monitoring without the need for a dedicated atrial lead. OBJECTIVE: To establish the reaction to and timing of reactions to the detection of atrial high rate episodes (AHRE). METHODS: A prospective cohort of DX ICD systems was followed up and the response to AHREs was collected and evaluated. RESULTS: A total of 234 patients were enrolled; an AHRE ⩾ 6 min was detected in 13.7% of patients (n= 32) within a mean follow-up duration of 16 months. A high rate of oral anticoagulation (OAC) prescription was seen with the detection of AHREs in patients with a not-low risk CHA2DS2-VASc score. There was a delay in this prescription highlighting the potential to improve the timeliness of patient care in this group of patients. CONCLUSIONS: The DX ICD system provides rapid and ongoing atrial rhythm monitoring such that physicians are rapidly aware of AHRE without the need for a dedicated atrial lead, but local protocols are needed to improve the response time of anti-coagulation prescription.

5. Trace elements, dioxins and PCBs in different fish species and marine regions: Importance of the taxon and regional features.

   Aourell Mauffret, Tiphaine Chouvelon, Nathalie Wessel, and 10 more authors

   Environmental research, Jan 2023

   Place: Netherlands

   Abs Link

   Chemical contaminant concentrations in wild organisms are used to assess environmental status under the European Marine Strategy Framework Directive. However, this approach is challenged by the complex intra- and inter-species variability, and the different regional features. In this study, concentrations in trace elements (As, Cd, Hg and Pb), polychlorinated biphenyls (PCBs), polychlorodibenzo-para-dioxines (PCDDs) and polychlorodibenzofuranes (PCDFs) were monitored in 8 fish species sampled on the continental shelf of three French regions: the Eastern English Channel (EEC) and Bay of Biscay (BoB) in the Northeast Atlantic Ocean, and the Gulf of Lions (GoL) in Western Mediterranean Sea. Our objectives were to identify species or regions more likely to be contaminated and to assess how to take this variability into account in environmental assessment. While concentrations were higher in benthic and demersal piscivores, PCB and PCDD/F concentrations (lipid-weight) were similar in most teleost species. For Cd, Hg and Pb, the trophic group accumulating the highest concentrations depended on the contaminant and region. Concentrations in Hg, PCBs and PCDD/Fs were higher in the EEC and/or GoL than in BoB. Cadmium and Pb concentrations were highest in the BoB. Lipid content accounted for 35%-84% of organic contaminant variability. Lipid normalisation was employed to enhance robustness in the identification of spatial patterns. Contaminant patterns in chondrichthyans clearly differed from that in teleosts. In addition, trophic levels accounted for ≤1% and ≤33% of the contaminant variability in teleost fishes in the EEC and BoB, respectively. Therefore, developing taxa-specific thresholds might be a more practical way forward for environmental assessment than normalisation to trophic levels.

6. Development of an integrated indicator to assess chemical contamination in different marine species: The case of mercury on the French Atlantic continental shelf.

   Tiphaine Mille, Nathalie Wessel, Mélanie Brun, and 6 more authors

   The Science of the total environment, Dec 2023

   Place: Netherlands

   Abs Link

   Good Environmental Status (GES) for Descriptor 8 (D8) of the Marine Strategy Framework Directive (MSFD) is considered to be achieved when concentrations of contaminants are at levels not giving rise to pollution effects. This study proposes a framework to assess GES in marine waters adjacent to France, including four groups of species (bivalves, fish, birds and mammals) living on the continental shelf and covering different dimensions of the marine environment. This framework is applied to mercury (Hg) in the three marine regions along the French Atlantic coast and includes two assessment types: i) an absolute assessment by comparing contamination levels with environmental thresholds, and ii) a relative assessment by comparing contamination levels over time, performed for bivalves and mammals that had long time-series available. Mercury concentrations were higher than environmental thresholds for bivalves and fish in all the three studied regions. Plus, they significantly increased since the 2000s for most bivalve stations and for the common dolphin Delphinus delphis. Our results therefore indicate that Hg concentrations have increased in marine waters and have reached levels possibly giving rise to pollution effects in biota from the three marine regions. The present study also highlighted the complementarity of monitoring Hg concentrations in each group of species and each type of assessment, making it possible to propose a conceptual framework for assessing the environmental pressure of bioaccumulated and biomagnified contaminants over the continental shelf.

7. Intraoperative Beat-to-Beat Pulse Transit Time (PTT) Monitoring via Non-Invasive Piezoelectric/Piezocapacitive Peripheral Sensors Can Predict Changes in Invasively Acquired Blood Pressure in High-Risk Surgical Patients.

   Michael Nordine, Marius Pille, Jan Kraemer, and 7 more authors

   Sensors (Basel, Switzerland), Mar 2023

   Place: Switzerland

   Abs Link

   BACKGROUND: Non-invasive tracking of beat-to-beat pulse transit time (PTT) via piezoelectric/piezocapacitive sensors (PES/PCS) may expand perioperative hemodynamic monitoring. This study evaluated the ability for PTT via PES/PCS to correlate with systolic, diastolic, and mean invasive blood pressure (SBP(IBP), DBP(IBP), and MAP(IBP), respectively) and to detect SBP(IBP) fluctuations. METHODS: PES/PCS and IBP measurements were performed in 20 patients undergoing abdominal, urological, and cardiac surgery. A Pearson’s correlation analysis (r) between 1/PTT and IBP was performed. The predictive ability of 1/PTT with changes in SBP(IBP) was determined by area under the curve (reported as AUC, sensitivity, specificity). RESULTS: Significant correlations between 1/PTT and SBP(IBP) were found for PES (r = 0.64) and PCS (r = 0.55) (p \textless 0.01), as well as MAP(IBP)/DBP(IBP) for PES (r = 0.6/0.55) and PCS (r = 0.5/0.45) (p \textless 0.05). A 7% decrease in 1/PTT(PES) predicted a 30% SBP(IBP) decrease (0.82, 0.76, 0.76), while a 5.6% increase predicted a 30% SBP(IBP) increase (0.75, 0.7, 0.68). A 6.6% decrease in 1/PTT(PCS) detected a 30% SBP(IBP) decrease (0.81, 0.72, 0.8), while a 4.8% 1/PTT(PCS) increase detected a 30% SBP(IBP) increase (0.73, 0.64, 0.68). CONCLUSIONS: Non-invasive beat-to-beat PTT via PES/PCS demonstrated significant correlations with IBP and detected significant changes in SBP(IBP). Thus, PES/PCS as a novel sensor technology may augment intraoperative hemodynamic monitoring during major surgery.

2021

1. The Different Facets of Heart Rate Variability in Obstructive Sleep Apnea.

   Hua Qin, Nicolas Steenbergen, Martin Glos, and 4 more authors

   Frontiers in psychiatry, Mar 2021

   Place: Switzerland

   Abs Link

   Obstructive sleep apnea (OSA), a heterogeneous and multifactorial sleep related breathing disorder with high prevalence, is a recognized risk factor for cardiovascular morbidity and mortality. Autonomic dysfunction leads to adverse cardiovascular outcomes in diverse pathways. Heart rate is a complex physiological process involving neurovisceral networks and relative regulatory mechanisms such as thermoregulation, renin-angiotensin-aldosterone mechanisms, and metabolic mechanisms. Heart rate variability (HRV) is considered as a reliable and non-invasive measure of autonomic modulation response and adaptation to endogenous and exogenous stimuli. HRV measures may add a new dimension to help understand the interplay between cardiac and nervous system involvement in OSA. The aim of this review is to introduce the various applications of HRV in different aspects of OSA to examine the impaired neuro-cardiac modulation. More specifically, the topics covered include: HRV time windows, sleep staging, arousal, sleepiness, hypoxia, mental illness, and mortality and morbidity. All of these aspects show pathways in the clinical implementation of HRV to screen, diagnose, classify, and predict patients as a reasonable and more convenient alternative to current measures.

2. Automatic Sleep Staging in Children with Sleep Apnea using Photoplethysmography and Convolutional Neural Networks.

   Fernando Vaquerizo-Villar, Daniel Alvarez, Jan F. Kraemer, and 8 more authors

   Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference, Nov 2021

   Place: United States

   Abs Link

   Sleep staging is of paramount importance in children with suspicion of pediatric obstructive sleep apnea (OSA). Complexity, cost, and intrusiveness of overnight polysomnography (PSG), the gold standard, have led to the search for alternative tests. In this sense, the photoplethysmography signal (PPG) carries useful information about the autonomous nervous activity associated to sleep stages and can be easily acquired in pediatric sleep apnea home tests with a pulse oximeter. In this study, we use the PPG signal along with convolutional neural networks (CNN), a deep-learning technique, for the automatic identification of the three main levels of sleep: wake (W), rapid eye movement (REM), and non-REM sleep. A database of 366 PPG recordings from pediatric OSA patients is involved in the study. A CNN architecture was trained using 30-s epochs from the PPG signal for three-stage sleep classification. This model showed a promising diagnostic performance in an independent test set, with 78.2% accuracy and 0.57 Cohen’s kappa for W/NREM/REM classification. Furthermore, the percentage of time in wake stage obtained for each subject showed no statistically significant differences with the manually scored from PSG. These results were superior to the only state-of-the-art study focused on the analysis of the PPG signal in the automated detection of sleep stages in children suffering from OSA. This suggests that CNN can be used along with PPG recordings for sleep stages scoring in pediatric home sleep apnea tests.

3. Heart rate variability during wakefulness as a marker of obstructive sleep apnea severity.

   Hua Qin, Brendan T. Keenan, Diego R. Mazzotti, and 16 more authors

   Sleep, May 2021

   Place: United States

   Abs Link

   STUDY OBJECTIVES: Patients with obstructive sleep apnea (OSA) exhibit heterogeneous heart rate variability (HRV) during wakefulness and sleep. We investigated the influence of OSA severity on HRV parameters during wakefulness in a large international clinical sample. METHODS: 1247 subjects (426 without OSA and 821 patients with OSA) were enrolled from the Sleep Apnea Global Interdisciplinary Consortium. HRV parameters were calculated during a 5-minute wakefulness period with spontaneous breathing prior to the sleep study, using time-domain, frequency-domain and nonlinear methods. Differences in HRV were evaluated among groups using analysis of covariance, controlling for relevant covariates. RESULTS: Patients with OSA showed significantly lower time-domain variations and less complexity of heartbeats compared to individuals without OSA. Those with severe OSA had remarkably reduced HRV compared to all other groups. Compared to non-OSA patients, those with severe OSA had lower HRV based on SDNN (adjusted mean: 37.4 vs. 46.2 ms; p \textless 0.0001), RMSSD (21.5 vs. 27.9 ms; p \textless 0.0001), ShanEn (1.83 vs. 2.01; p \textless 0.0001), and Forbword (36.7 vs. 33.0; p = 0.0001). While no differences were found in frequency-domain measures overall, among obese patients there was a shift to sympathetic dominance in severe OSA, with a higher LF/HF ratio compared to obese non-OSA patients (4.2 vs. 2.7; p = 0.009). CONCLUSIONS: Time-domain and nonlinear HRV measures during wakefulness are associated with OSA severity, with severe patients having remarkably reduced and less complex HRV. Frequency-domain measures show a shift to sympathetic dominance only in obese OSA patients. Thus, HRV during wakefulness could provide additional information about cardiovascular physiology in OSA patients. CLINICAL TRIAL INFORMATION: A Prospective Observational Cohort to Study the Genetics of Obstructive Sleep Apnea and Associated Co-Morbidities (German Clinical Trials Register - DKRS, DRKS00003966) https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00003966.

4. Measurement of multiple cytokines for discrimination and risk stratification in patients with Chagas’ disease and idiopathic dilated cardiomyopathy.

   Yong Wang, Niels Wessel, Franziska Kohse, and 4 more authors

   PLoS neglected tropical diseases, Mar 2021

   Place: United States

   Abs Link

   Chagas’ disease (CD), caused by the hemoflagellate protozoan, Trypanosoma cruzi, is endemic in most countries of Latin America. Heart failure (HF) is often a late manifestation of chronic CD, and is associated with high morbidity and mortality. Inflammatory processes mediated by cytokines play a key role in the pathogenesis and progression of CD. Keeping in view the inflammatory nature of CD, this study investigated the possible role of 21 different inflammatory cytokines as biomarkers for prediction and prognosis of CD. The plasma concentration of these cytokines was measured in a group of patients with CD (n = 94), and then compared with those measured in patients with dilated cardiomyopathy (DCM) from idiopathic causes (n = 48), and with control subjects (n = 25). Monovariately, plasma levels of cytokines such as stem cell growth factor beta (SCGF beta), hepatocyte growth factor (HGF), monokine induced by interferon gamma (CXCL9), and macrophage inhibitory factor (MIF) were significantly increased in CD patients with advanced HF compared to control group. None of the cytokines could demonstrate any prognostic potency in CD patients, and only MIF and stromal derived factor-1 alpha (CXCL12) showed significance in predicting mortality and necessity for heart transplant in DCM patients. However, multivariate analysis prognosticated a large proportion of CD and DCM patients. In CD patients, HGF and Interleukin-12p40 (IL-12p40) together separated 81.9% of 3-year survivors from the deceased, while in DCM patients, CXCL12, stem cell factor (SCF), and CXCL9 together discriminated 77.1% of survivors from the deceased. The significant increase in plasma concentrations of cytokines such as HGF and CXCL9 in CD patients, and the ability of these cytokines to prognosticate a large proportion of CD and DCM patients multivariately, encourages further studies to clarify the diagnostic and prognostic potential of cytokines in such patients.

2020

1. Transportation noise impairs cardiovascular function without altering sleep: The importance of autonomic arousals.

   Laurie Thiesse, Franziska Rudzik, Jan F. Kraemer, and 14 more authors

   Environmental research, Mar 2020

   Place: Netherlands

   Abs Link

   AIMS: Chronic exposure to nocturnal transportation noise has been linked to cardiovascular disorders with sleep impairment as the main mediator. Here we examined whether nocturnal transportation noise affects the main stress pathways, and whether it relates to changes in the macro and micro structure of sleep. METHODS AND RESULTS: Twenty-six young healthy participants (12 women, 24.6 ± 0.7 years, mean ± SE) spent five consecutive 24-h days and one last morning in the laboratory. The first (baseline) and last (recovery) nights comprised a quiet ambient scenario. In-between, four different noise scenarios (low/medium/high intermittent road or rail scenarios with an identical equivalent continuous sound level of 45 dB) were randomly presented during the 8-h nights. Participants felt more annoyed from the transportation noise scenarios compared to the quiet ambient scenario played back during the baseline and recovery nights (F(5,117) = 10.2, p \textless 0.001). Nocturnal transportation noise did not significantly impact polysomnographically assessed sleep macrostructure, blood pressure, nocturnal catecholamine levels and morning cytokine levels. Evening cortisol levels increased after sleeping with highly intermittent road noise compared to baseline (p = 0.002, noise effect: F(4,83) = 4.0, p = 0.005), a result related to increased cumulative duration of autonomic arousals during the noise nights (F(5,106) = 3.4, p \textless 0.001; correlation: r(pearson) = 0.64, p = 0.006). CONCLUSION: Under controlled laboratory conditions, highly intermittent nocturnal road noise exposure at 45 dB increased the cumulative duration of autonomic arousals during sleep and next-day evening cortisol levels. Our results indicate that, without impairing sleep macrostructure, nocturnal transportation noise of 45 dB is a physiological stressor that affects the hypothalamic-pituitary-adrenal axis during the following day in healthy young good sleepers.

2. Cardiac Autonomic Dysfunction and Incidence of de novo Atrial Fibrillation: Heart Rate Variability vs. Heart Rate Complexity.

   Niels Wessel, Karsten Berg, Jan F. Kraemer, and 10 more authors

   Frontiers in physiology, Mar 2020

   Place: Switzerland

   Abs Link

   BACKGROUND: The REACT DX registry evaluates standard therapies to episodes of long-lasting atrial tachyarrhythmias and assesses the quality of sensing and stability of the lead and the implantable cardioverter-defibrillator (ICD) (BIOTRONIK Lumax VR-T DX and successors) over at least a 1-year follow-up period. OBJECTIVE: To study the association between the risk of de novo device-detected atrial fibrillation (AF), the autonomic perturbations before the onset of paroxysmal AF and a 7-days heart rate variability (7dHRV) 1 month after ICD implantation. METHODS: The registry consists of 234 patients implanted with an ICD, including 10 with de novo long-lasting atrial tachyarrhythmias with no prior history of AF. The patients were matched via the propensity-score methodology as well as for properties directly influencing the ECGs recorded using GE CardioMem CM 3000. Heart rate variability (HRV) analysis was performed using standard parameters from time- and frequency-domains, and from non-linear dynamics. RESULTS: No linear HRV was associated with an increased risk of AF (p = n.s.). The only significant approach was derived from symbolic dynamics with the parameter "forbidden words" which distinguished both groups on all 7 days of measurements (p \textless 0.05), thereby quantifying the heart rate complexity (HRC) as drastically lower in the de novo AF group. CONCLUSION: Cardiac autonomic dysfunction denoted by low HRC may be associated with higher AF incidence. For patients with mild to moderate heart failure, standard HRV parameters are not appropriate to quantify cardiac autonomic perturbations before the onset of AF. Further studies are needed to determine the individual risk for AF that would enable interventions to restore autonomic balance in the general population.

3. Instantaneous Cardiac Baroreflex Sensitivity: xBRS Method Quantifies Heart Rate Blood Pressure Variability Ratio at Rest and During Slow Breathing.

   Niels Wessel, Andrej Gapelyuk, Jonas Weiß, and 6 more authors

   Frontiers in neuroscience, Mar 2020

   Place: Switzerland

   Abs Link

   Spontaneous baroreflex sensitivity (BRS) is a widely used tool for the quantification of the cardiovascular regulation. Numerous groups use the xBRS method, which calculates the cross-correlation between the systolic beat-to-beat blood pressure and the R-R interval (resampled at 1 Hz) in a 10 s sliding window, with 0-5 s delays for the interval. The delay with the highest correlation is selected and, if significant, the quotient of the standard deviations of the R-R intervals and the systolic blood pressures is recorded as the corresponding xBRS value. In this paper we test the hypothesis that the xBRS method quantifies the causal interactions of spontaneous BRS from non-invasive measurements at rest. We use the term spontaneous BRS in the sense of the sensitivity curve is calculated from non-interventional, i.e., spontaneous, baroreceptor activity. This study includes retrospective analysis of 1828 measurements containing ECG as well as continues blood pressure under resting conditions. Our results show a high correlation between the heart rate - systolic blood pressure variability (HRV/BPV) quotient and the xBRS (r = 0.94, p \textless 0.001). For a deeper understanding we conducted two surrogate analyses by substituting the systolic blood pressure by its reversed time series. These showed that the xBRS method was not able to quantify causal relationships between the two signals. It was not possible to distinguish between random and baroreflex controlled sequences. It appears xBRS rather determines the HRV/BPV quotient. We conclude that the xBRS method has a potentially large bias in characterizing the capacity of the arterial baroreflex under resting conditions. During slow breathing, estimates for xBRS are significantly increased, which clearly shows that measurements at rest only involve limited baroreflex activity, but does neither challenge, nor show the full range of the arterial baroreflex regulatory capacity. We show that xBRS is exclusively dominated by the heart rate to systolic blood pressure ratio (r = 0.965, p \textless 0.001). Further investigations should focus on additional autonomous testing procedures such as slow breathing or orthostatic testing to provide a basis for a non-invasive evaluation of baroreflex sensitivity.

4. Spontaneous baroreflex sensitivity: sequence method at rest does not quantify causal interactions but rather determines the heart rate to blood pressure variability ratio.

   N. Wessel, A. Gapelyuk, J. F. Kraemer, and 2 more authors

   Physiological measurement, Apr 2020

   Place: England

   Link
5. Comparison of fetal heart rate variability by symbolic dynamics at the third trimester of pregnancy and low-risk parturition.

   Cristian Iván Montalvo-Jaramillo, Adriana Cristina Pliego-Carrillo, Miguel Ángel Peña-Castillo, and 9 more authors

   Heliyon, Mar 2020

   Place: England

   Abs Link

   Fetal heart rate variability (fHRV) is an essential source of information to monitor fetal well-being during pregnancy. This study aimed to apply a nonlinear approach, known as symbolic dynamics (SD), for comparing human fHRV in the third trimester of pregnancy during active fetal state (TT) and active labor at term (P). We performed a longitudinal, prospective, descriptive, and comparative study composed of 42 longitudinal recordings of 5-minutes of fetal heartbeat interval series. Recordings were collected from 21 low-risk, healthy, pregnant women attending the Maternal and Child Research Center (CIMIGen), Mexico City. We calculated relevant linear parameters of fHRV between TT and P stages, such as the percentage of differences between adjacent RR intervals \textgreater5 ms (PRR5, related to vagal modulations) and other SD parameters such as the percentage of no variations between three successive symbols (%0V, reflects sympathetic modulations) and the probability of low variability with a threshold of 4 ms (POLVAR4, associated with a low variability). We identified statistical differences for PRR5 between TT and P (37.13% [28.47-47.60%] vs. 28.84% [19.36-36.76%], p = 0.03), respectively. Also, for 0V% (65.66% [59.01-71.80%] vs. 71.14% [65.94-75.87%], p = 0.03) and for POLVAR4 values (0.06 [0.04-0.11] vs. 0.15 [0.09-0.24], p = 0.002), respectively. Our results indicate that during parturition, the short-term fetal fHRV is decreased, showing a decreased vagal modulations and higher adrenergic response of the heart. These autonomic modifications may result from the fetal response to the stressful inflammatory challenge of labor. We thus confirmed that the analysis of the SD applied to fHRV time series could be a potential clinical biomarker to differentiate the fetal autonomic cardiac condition at different stages of pregnancy.

6. Prediction of Sudden Cardiac Death Risk with a Support Vector Machine Based on Heart Rate Variability and Heartprint Indices.

   Marisol Martinez-Alanis, Erik Bojorges-Valdez, Niels Wessel, and 1 more author

   Sensors (Basel, Switzerland), Sep 2020

   Place: Switzerland

   Abs Link

   Most methods for sudden cardiac death (SCD) prediction require long-term (24 h) electrocardiogram recordings to measure heart rate variability (HRV) indices or premature ventricular complex indices (with the heartprint method). This work aimed to identify the best combinations of HRV and heartprint indices for predicting SCD based on short-term recordings (1000 heartbeats) through a support vector machine (SVM). Eleven HRV indices and five heartprint indices were measured in 135 pairs of recordings (one before an SCD episode and another without SCD as control). SVMs (defined with a radial basis function kernel with hyperparameter optimization) were trained with this dataset to identify the 13 best combinations of indices systematically. Through 10-fold cross-validation, the best area under the curve (AUC) value as a function of γ (gamma) and cost was identified. The predictive value of the identified combinations had AUCs between 0.80 and 0.86 and accuracies between 80 and 86%. Further SVM performance tests on a different dataset of 68 recordings (33 before SCD and 35 as control) showed AUC = 0.68 and accuracy = 67% for the best combination. The developed SVM may be useful for preventing imminent SCD through early warning based on electrocardiogram (ECG) or heart rate monitoring.

2019

1. Symbolic analysis of heart rate fluctuations identifies cardiac autonomic modifications during LPS-induced endotoxemia.

   José Javier Reyes-Lagos, Claudia Ivette Ledesma-Ramírez, Martin Hadamitzky, and 7 more authors

   Autonomic neuroscience : basic & clinical, Nov 2019

   Place: Netherlands

   Abs Link

   The present study aimed to compare linear and symbolic dynamics (SD) indices for detecting the autonomic cardiac changes produced by endotoxemia in freely-moving rats. In this context, we analyzed ECG-derived R-R time series in freely moving Dark Agouti rats, which received lipopolysaccharide (LPS, n = 9), or vehicle (V, n = 7). Five minutes R-R time series were assessed every hour up to +12 h and + 24 h post-LPS injection. We found that SD indices showed significant differences at +7 h between V vs. LPS groups and at +9 h between basal levels of LPS (-3 h) and post-LPS injection (pre-LPS vs. post-LPS). In general, SD seems more appropriate than linear indices to evaluate the autonomic changes of endotoxemic rats. Overall, the symbolic parameters detected decreased R-R variability and complexity, which indicate a modification of the autonomic regulation during LPS-induced endotoxemia. This modification is probably related to a reduced activity of the cholinergic anti-inflammatory pathway at the long term.

2. Utilization of venous thromboembolism prophylaxis in American hospitalized pregnant women undergoing cesarean section.

   Tiffany K. Pon, Natalie Wessel, Vincent Cagonot, and 3 more authors

   International journal of clinical pharmacy, Feb 2019

   Place: Netherlands

   Abs Link

   Background Pregnancy-related venous thromboembolism (VTE) is a leading preventable cause of maternal mortality in the United States; however, American guidelines for pharmacologic VTE prophylaxis remain less aggressive than other developed countries. The Safe Motherhood Initiative (SMI) combines aspects of American and international guidelines to increase utilization of prophylaxis and thereby decrease incidence of pregnancy-related VTE. Objectives To evaluate the prescribing and administration rates of pharmacologic VTE prophylaxis for women undergoing cesarean section (c-section) when retrospectively applying the SMI recommendations. Setting Large academic medical center in Sacramento, California, USA. Method This was a single-center retrospective cohort study of pregnant women undergoing c-section who would have met criteria for pharmacologic prophylaxis according to the SMI. Main outcome measures Prescribing and administration rates of mechanical and pharmacologic VTE prophylaxis. Secondary outcomes included incidence of thromboembolism within 6 weeks after c-section and thromboembolic associated mortality. Results A total of 616 charts were analyzed. When applying the SMI guidelines for VTE prophylaxis, the prescribing rates for mechanical and pharmacologic prophylaxis were 94.3% and 4.71% of patients, respectively, and 94.9% of ordered pharmacologic prophylaxis doses were administered. The incidence of 6-week post-partum VTE was 0.49%. There were no cases of VTE-associated mortality. Conclusion This study demonstrated that a large population of c-section patients fit the SMI criteria for pharmacologic VTE prophylaxis but did not receive it. We observed a 0.49% rate of VTE, which was slightly higher than the nationally reported average rate of 0.3%. With growing rates of pregnancy-associated VTE in the United States, perhaps a more aggressive guideline is warranted.

3. Screening for Obstructive Sleep Apnea in Commercial Drivers Using EKG-Derived Respiratory Power Index.

   M. Melani Lyons, Jan F. Kraemer, Radha Dhingra, and 5 more authors

   Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, Jan 2019

   Place: United States

   Abs Link

   STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is common in commercial motor vehicle operators (CMVOs); however, polysomnography (PSG), the gold-standard diagnostic test, is expensive and inconvenient for screening. OSA is associated with changes in heart rate and voltage on electrocardiography (EKG). We evaluated the utility of EKG parameters in identifying CMVOs at greater risk for sleepiness-related crashes (apnea-hypopnea index [AHI] ≥ 30 events/h). METHODS: In this prospective study of CMVOs, we performed EKGs with concurrent PSG, and calculated the respiratory power index (RPI) on EKG, a surrogate for AHI calculated from PSG. We evaluated the utility of two-stage predictive models using simple clinical measures (age, body mass index [BMI], neck circumference, Epworth Sleepiness Scale score, and the Multi-Variable Apnea Prediction [MVAP] score) in the first stage, followed by RPI in a subset as the second-stage. We assessed area under the receiver operating characteristic curve (AUC), sensitivity, and negative posttest probability (NPTP) for this two-stage approach and for RPI alone. RESULTS: The best-performing model used the MVAP, which combines BMI, age, and sex with three OSA symptoms, in the first stage, followed by RPI in the second. The model yielded an estimated (95% confidence interval) AUC of 0.883 (0.767-0.924), sensitivity of 0.917 (0.706-0.962), and NPTP of 0.034 (0.015-0.133). Predictive characteristics were similar using a model with only BMI as the first-stage screen. CONCLUSIONS: A two-stage model that combines BMI or the MVAP score in the first stage, with EKG in the second, had robust discriminatory power to identify severe OSA in CMVOs.

2018

1. Is dynamic desaturation better than a static index to quantify the mortality risk in heart failure patients with Cheyne-Stokes respiration?

   Philine Granitza, Jan F. Kraemer, Christoph Schoebel, and 3 more authors

   Chaos (Woodbury, N.Y.), Oct 2018

   Place: United States

   Abs Link

   Cheyne-Stokes respiration (CSR) is a periodic, highly dynamic, respiratory pattern and a known comorbidity in congestive heart failure (CHF) patients. It is generally seen as an indicator for a negative prognosis, even if no distinction in degree is known or understood. This paper aims to improve on existing attempts by creating a quantification of the behavior of the dynamic desaturation process of oxygen in the blood. We performed this work on a cohort of 11 subjects with CHF, reduced left ventricular ejection fraction, and CSR. The dynamic desaturation process was evaluated according to changes to peripheral capillary oxygenation SpO2 resulting from highly nonlinear relationships in the ventilatory system perturbed by periodic breathing. Hypoxaemic burden expressed as a static index T90 was compared to a novel relative desaturation index RDI , developed in this paper. While T90 represents a single value calculated using a static cut-off value of 90% SpO2 , the RDI is more sensitive to dynamic influences as it uses the specific maximum change in saturation for each CSR episode. The threshold of T90 = 22 min per night as suggested by Oldenburg et al. could not be confirmed to predict survival, but all central apneas resulting in a relative desaturation of SpO2 above a cut-off value of 8% were a 100% positive predictor of mortality. The RDI proved sufficiently stable in intraindividual measurements across CSR epochs. Across the cohort, it showed a bimodal distribution for the deceased group, indicative of a possible aetiological difference. Hence, it is our conclusion that a dynamic approach to analyse desaturation of oxygen during Cheyne-Stokes respiration is to be strongly favoured over a static approach to analysis.

2. Angiotensin-(1-7) Receptor Mas in Hemodynamic and Thermoregulatory Dysfunction After High-Level Spinal Cord Injury in Mice: A Pilot Study.

   Anne Järve, Mihail Todiras, Melanie Kny, and 7 more authors

   Frontiers in physiology, Oct 2018

   Place: Switzerland

   Abs Link

   Spinal cord injury (SCI) above mid-thoracic levels leads to autonomic dysfunction affecting both the cardiovascular system and thermoregulation. The renin-angiotensin system (RAS) which is a potent regulator of blood pressure, including its novel beneficial arm with the receptor Mas could be an interesting target in post-SCI hemodynamics. To test the hypothesis that hemodynamics, activity and diurnal patterns of those are more affected in the Mas deficient mice post-SCI we used a mouse model of SCI with complete transection of spinal cord at thoracic level 4 (T4-Tx) and performed telemetric monitoring of blood pressure (BP) and heart rate (HR). Our data revealed that hypothermia deteriorated physiological BP and HR control. Preserving normothermia by keeping mice at 30°C prevented severe hypotension and bradycardia post-SCI. Moreover, it facilitated rapid return of diurnal regulation of BP, HR and activity in wild type (WT) mice. In contrast, although Mas deficient mice had comparable reacquisition of diurnal HR rhythm, they showed delayed recovery of diurnal rhythmicity in BP and significantly lower nocturnal activity. Exposing mice with T4-Tx (kept in temperature-controlled cages) to 23°C room temperature for one hour at different time-points post-SCI, demonstrated their inability to maintain core body temperature, Mas deficient mice being significantly more impaired than WT littermates. We conclude that Mas deficient mice were more resistant to acute hypotension, delayed nocturnal recovery, lower activity and more severely impaired thermoregulation. The ambient temperature had significant effect on hemodynamics and, thus it should be taken into account when assessing cardiovascular parameters post-SCI in mice.

2017

1. Recent advances in physiological oscillations.

   Thomas Penzel, Alberto Porta, Aneta Stefanovska, and 1 more author

   Physiological measurement, May 2017

   Place: England

   Link
2. On the difference of cardiorespiratory synchronisation and coordination.

   Harald Krause, Jan F. Kraemer, Thomas Penzel, and 2 more authors

   Chaos (Woodbury, N.Y.), Sep 2017

   Place: United States

   Abs Link

   Cardiorespiratory phase synchronisation (CRS) is a type of cardiorespiratory coupling that manifests through a prediliction for heart beats to occur at specific points relative to the phase of the respiratory cycle. It has been under investigation for nearly 20 years, and while it seems to be mostly occurring in relaxed states such as deep sleep and anesthesia, no clear clinical implications have been established. Cardiorespiratory coordination (CRC) is a recent development in this field where the relationship between the respiratory onset and heart beat is analysed in the time domain and the possible relationship of each heart beat is considered for both the previous and the next respiratory onset. This ostensibly closely related effect must not only show relevant information content but also do so independent of CRS in order to be relevant for future studies. In this paper, we investigate CRC and its relation to CRS mainly using graphical and statistical methods on two exemplary datasets: measurements from a pregnant woman participating in a preeclampsia study and those from a man suffering from sleep apnea. We show fundamental differences between the results of both approaches and are able to show a formerly unknown dependency between the heart activity and respiratory rate, potentially indicating heartbeat-initiated inspiration. Despite their differences, methods developed for the quantification of CRS can be adapted to CRC. Completing the comparison is an investigation into the relationship between CRC and respiratory sinus arrhythmia. Similar to previous results for CRS, the two effects are found to be orthogonal, meaning that they can be observed independently or in conjunction.

3. Increased cardiorespiratory coordination in preeclampsia.

   Karsten Berg, Jan F. Kraemer, Maik Riedl, and 3 more authors

   Physiological measurement, May 2017

   Place: England

   Abs Link

   Preeclampsia is one of the main sources of morbidity in pregnancy with a high mortality rate without a known ultimate cause. Using a corpus including 927 measurements of pregnant women with and without different hypertonic diseases at multiple stages of pregnancy, we utilised a new approach to analyse cardiorespiratory coordination. Since the recording quality of respiratory effort was limited due to a high signal to noise ratio, we applied an ECG derived respiration approach to create an ersatz respiratory signal. After applying the few available recordings with a sufficiently high quality of the respiratory signal to validate the substitute, coordigrams were calculated and quantified by utilising an epsilon method. We showed significant (p  \textless  0.05) differences in the coordination in a matched (BMI, age, gestational week) comparison of preeclamptic and healthy subjects. Hopefully future applications of and improvements on these methods are able to create a fast and convenient prediction methodology to reduce the impact of this disease as well as help in the determination of its underlying cause.

4. Quantifying Effects of Pharmacological Blockers of Cardiac Autonomous Control Using Variability Parameters.

   Renata Miyabara, Karsten Berg, Jan F. Kraemer, and 3 more authors

   Frontiers in physiology, May 2017

   Place: Switzerland

   Abs Link

   Objective: The aim of this study was to identify the most sensitive heart rate and blood pressure variability (HRV and BPV) parameters from a given set of well-known methods for the quantification of cardiovascular autonomic function after several autonomic blockades. Methods: Cardiovascular sympathetic and parasympathetic functions were studied in freely moving rats following peripheral muscarinic (methylatropine), β1-adrenergic (metoprolol), muscarinic + β1-adrenergic, α1-adrenergic (prazosin), and ganglionic (hexamethonium) blockades. Time domain, frequency domain and symbolic dynamics measures for each of HRV and BPV were classified through paired Wilcoxon test for all autonomic drugs separately. In order to select those variables that have a high relevance to, and stable influence on our target measurements (HRV, BPV) we used Fisher’s Method to combine the p-value of multiple tests. Results: This analysis led to the following best set of cardiovascular variability parameters: The mean normal beat-to-beat-interval/value (HRV/BPV: meanNN), the coefficient of variation (cvNN = standard deviation over meanNN) and the root mean square differences of successive (RMSSD) of the time domain analysis. In frequency domain analysis the very-low-frequency (VLF) component was selected. From symbolic dynamics Shannon entropy of the word distribution (FWSHANNON) as well as POLVAR3, the non-linear parameter to detect intermittently decreased variability, showed the best ability to discriminate between the different autonomic blockades. Conclusion: Throughout a complex comparative analysis of HRV and BPV measures altered by a set of autonomic drugs, we identified the most sensitive set of informative cardiovascular variability indexes able to pick up the modifications imposed by the autonomic challenges. These indexes may help to increase our understanding of cardiovascular sympathetic and parasympathetic functions in translational studies of experimental diseases.

5. Heart rate variability feature selection in the presence of sleep apnea: An expert system for the characterization and detection of the disorder.

   Sofía Martín-González, Juan L. Navarro-Mesa, Gabriel Juliá-Serdá, and 3 more authors

   Computers in biology and medicine, Dec 2017

   Place: United States

   Abs Link

   We introduce a sleep apnea characterization and classification approach based on a Heart Rate Variability (HRV) feature selection process, thus focusing on the characterization of the underlying process from a cardiac rate point of view. Therefore, we introduce linear and nonlinear variables, namely Cepstrum Coefficients (CC), Filterbanks (Fbank) and Detrended Fluctuation Analysis (DFA). Logistic Regression, Linear Discriminant Analysis and Quadratic Discriminant Analysis were used for classification purposes. The experiments were carried out using two databases. We achieved a per-segment accuracy of 84.76% (sensitivity = 81.45%, specificity = 86.82%, AUC = 0.92) in the Apnea-ECG Physionet database, whereas in the HuGCDN2014 database, provided by the Dr. Negrín University Hospital (Las Palmas de Gran Canaria, Spain), the best results were: accuracy = 81.96%, sensitivity = 70.95%, specificity = 85.47%, AUC = 0.87. The former results were comparable or better than those obtained by other methods for the same database in the recent literature. We have concluded that the selected features that best characterize the underlying process are common to both databases. This supports the fact that the conclusions reached are potentially generalizable. The best results were obtained when the three kinds of features were jointly used. Another notable fact is the small number of features needed to describe the phenomenon. Results suggest that the two first Fbanks, the first CC and the first DFA coefficient are the variables that best describe the RR pattern in OSA and, therefore, are especially relevant to extract discriminative information for apnea screening purposes.

2016

1. Causality in physiological signals.

   Andreas Müller, Jan F. Kraemer, Thomas Penzel, and 3 more authors

   Physiological measurement, May 2016

   Place: England

   Abs Link

   Health is one of the most important non-material assets and thus also has an enormous influence on material values, since treating and preventing diseases is expensive. The number one cause of death worldwide today originates in cardiovascular diseases. For these reasons the aim of understanding the functions and the interactions of the cardiovascular system is and has been a major research topic throughout various disciplines for more than a hundred years. The purpose of most of today’s research is to get as much information as possible with the lowest possible effort and the least discomfort for the subject or patient, e.g. via non-invasive measurements. A family of tools whose importance has been growing during the last years is known under the headline of coupling measures. The rationale for this kind of analysis is to identify the structure of interactions in a system of multiple components. Important information lies for example in the coupling direction, the coupling strength, and occurring time lags. In this work, we will, after a brief general introduction covering the development of cardiovascular time series analysis, introduce, explain and review some of the most important coupling measures and classify them according to their origin and capabilities in the light of physiological analyses. We will begin with classical correlation measures, go via Granger-causality-based tools, entropy-based techniques (e.g. momentary information transfer), nonlinear prediction measures (e.g. mutual prediction) to symbolic dynamics (e.g. symbolic coupling traces). All these methods have contributed important insights into physiological interactions like cardiorespiratory coupling, neuro-cardio-coupling and many more. Furthermore, we will cover tools to detect and analyze synchronization and coordination (e.g. synchrogram and coordigram). As a last point we will address time dependent couplings as identified using a recent approach employing ensembles of time series. The scope of this review, as opposed to various other excellent reviews like (Hlaváčková-Schindler et al Phys. Rep. 441 1-46, Kramer et al 2004 Phys. Rev. E 70 1-10, Lombardi 2000 Circulation 101 8-10, Porta et al 2000 Am. J. Physiol.: Heart and Circulatory Physiol. 279 H2558-67, Schelter et al 2006 J. Neurosci. Methods 152 210-9), is to give a broader overview over existing coupling measures and where to look to find the most appropriate tool for a given situation. The review will comprise a test of one representative of the most important coupling measure groups using a simple toy model to illustrate some essential features of the tools. At the end we will summarise the performance of each measure and offer some advice on when to use which method.

2. Modulations of Heart Rate, ECG, and Cardio-Respiratory Coupling Observed in Polysomnography.

   Thomas Penzel, Jan W. Kantelhardt, Ronny P. Bartsch, and 7 more authors

   Frontiers in physiology, May 2016

   Place: Switzerland

   Abs Link

   The cardiac component of cardio-respiratory polysomnography is covered by ECG and heart rate recordings. However, their evaluation is often underrepresented in summarizing reports. As complements to EEG, EOG, and EMG, these signals provide diagnostic information for autonomic nervous activity during sleep. This review presents major methodological developments in sleep research regarding heart rate, ECG, and cardio-respiratory couplings in a chronological (historical) sequence. It presents physiological and pathophysiological insights related to sleep medicine obtained by new technical developments. Recorded nocturnal ECG facilitates conventional heart rate variability (HRV) analysis, studies of cyclical variations of heart rate, and analysis of ECG waveform. In healthy adults, the autonomous nervous system is regulated in totally different ways during wakefulness, slow-wave sleep, and REM sleep. Analysis of beat-to-beat heart-rate variations with statistical methods enables us to estimate sleep stages based on the differences in autonomic nervous system regulation. Furthermore, up to some degree, it is possible to track transitions from wakefulness to sleep by analysis of heart-rate variations. ECG and heart rate analysis allow assessment of selected sleep disorders as well. Sleep disordered breathing can be detected reliably by studying cyclical variation of heart rate combined with respiration-modulated changes in ECG morphology (amplitude of R wave and T wave).

3. Insomnia Characterization: From Hypnogram to Graph Spectral Theory.

   Ramiro Chaparro-Vargas, Beena Ahmed, Niels Wessel, and 2 more authors

   IEEE transactions on bio-medical engineering, Oct 2016

   Place: United States

   Abs Link

   OBJECTIVE: To quantify and differentiate control and insomnia sleep onset patterns through biomedical signal processing of overnight polysomnograms. METHODS: The approach consisted of three tandem modules: 1) biosignal processing module, which used state-space time-varying autoregressive moving average (TVARMA) processes with recursive particle filter, 2) hypnogram generation module that implemented a fuzzy inference system (FIS), and 3) insomnia characterization module that discriminated between control and subjects with insomnia using a logistic regression model trained with a set of similarity measures ( d1, d2 , d3, d4). The study employed sleep onset periods from 16 control and 16 subjects with insomnia. RESULTS: State-spaced TVARMA processes with recursive particle filtering provided resilience to nonlinear, nonstationary, and non-Gaussian conditions of biosignals. FIS managed automated sleep scoring robust to intersubjects’ and interraters’ variability. The similarity distances quantified in a scalar measure the transitions amongst sleep onset stages, computed from expert and automated hypnograms. A statistical set of unpaired two-tailed t -tests suggested that distances d1 , d2, and d3 had larger statistical significance ( ) to characterize sleeping patterns. The logistic regression model classified control and subjects with insomnia with sensitivity 87 % , specificity 75 %, and accuracy 81 %. CONCLUSION: Our approach can perform a supportive role in either biosignal processing, sleep staging, insomnia characterization, or all the previous, coping with time-consuming procedures and massive data volumes of standard protocols. SIGNIFICANCE: The introduction of graph spectral theory and logistic regression for the diagnosis of insomnia represents a novel concept, attempting to describe complex sleep dynamics throughout transitions networks and scalar measures.

4. Alpha-wave frequency characteristics in health and insomnia during sleep.

   Justus T. C. Schwabedal, Maik Riedl, Thomas Penzel, and 1 more author

   Journal of sleep research, Jun 2016

   Place: England

   Abs Link

   Appearances of alpha waves in the sleep electrencephalogram indicate physiological, brief states of awakening that lie in between wakefulness and sleep. These microstates may also cause the loss in sleep quality experienced by individuals suffering from insomnia. To distinguish such pathological awakenings from physiological ones, differences in alpha-wave characteristics between transient awakening and wakefulness observed before the onset of sleep were studied. In polysomnographic datasets of sleep-healthy participants (n = 18) and patients with insomnia (n = 10), alpha waves were extracted from the relaxed, wake state before sleep onset, wake after sleep-onset periods and arousals of sleep. In these, alpha frequency and variability were determined as the median and standard deviation of inverse peak-to-peak intervals. Before sleep onset, patients with insomnia showed a decreased alpha variability compared with healthy participants (P \textless 0.05). After sleep onset, both groups showed patterns of decreased alpha frequency that was lower for wake after sleep-onset periods of shorter duration. For patients with insomnia, alpha variability increased for short wake after sleep-onset periods. Major differences between the two groups were encountered during arousal. In particular, the alpha frequency in patients with insomnia rebounded to wake levels, while the frequency in healthy participants remained at the reduced level of short wake after sleep-onset periods. Reductions in alpha frequency during wake after sleep-onset periods may be related to the microstate between sleep and wakefulness that was described for such brief awakenings. Reduced alpha variability before sleep may indicate a dysfunction of the alpha generation mechanism in insomnia. Alpha characteristics may also prove valuable in the study of other sleep and attention disorders.

5. Reliability analysis of the heart autonomic control parameters during hemodialysis sessions.

   Débora Martins Silva, Murilo Carneiro Macedo, Lucas Brasileiro Lemos, and 5 more authors

   Biomedizinische Technik. Biomedical engineering, Dec 2016

   Place: Germany

   Abs Link

   The study of heart autonomic control (HAC) in patients with chronic kidney disease (CKD) undergoing dialysis treatment has been carried out, however, there are no studies reporting the reliability of measurements of HAC parameters involving the mentioned samples and conditions. The reliability of many HAC parameters was evaluated from patients with CKD during two sessions of hemodialysis. The successive R-R intervals were recorded during two sessions of hemodialysis from 14 CKD patients that were undergoing dialysis for at least 6 months and with no history of recurrent hypotensive events. HAC parameters were obtained with time and frequency domain analysis, as well as with nonlinear methods. The reliability was measured with the intraclass correlation coefficient (ICC). The results showed excellent reliability (ICC=0.90-0.98) for most heart rate variability (HRV) parameters, especially the parameters obtained in the time domain [square root of the mean squared differences between successive R-R intervals (RMSSD), percentage of adjacent R-R intervals that differ by more than 50 ms (pNN50), mean of the 5-min standard deviations of R-R intervals (SDNNi), and triangular index] and with non-linear methods [standard deviation of the instantaneous variability beat-to-beat (SD1), standard deviation in long-term continuous R-R intervals (SD2), detrended fluctuation analysis (DFA) α1 and α2, approximate and sample entropies, and correlation dimension (D2): ICC=0.86-0.96]. Among the parameters obtained in the frequency domain (normalized magnitude from the spectrum of low-frequency components (LFnu), normalized magnitude from the spectrum of high-frequency components (HFnu), and LF/HF ratio), the LF/HF ratio showed better reliability (ICC=0.96 vs. ICC=0.70). Measurements of HAC parameters have excellent test-retest reliability for the studied samples and conditions.

6. Assessing cardiac autonomic function via heart rate variability analysis requires monitoring respiration.

   N. Wessel, L. Sidorenko, J. F. Kraemer, and 2 more authors

   Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, Aug 2016

   Place: England

   Link
7. Standard heart rate variability spectral analysis: does it purely assess cardiac autonomic function?

   L. Sidorenko, J. F. Kraemer, and N. Wessel

   Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, Jul 2016

   Place: England

   Link

2015

1. Changes of sleep-stage transitions due to ageing and sleep disorder.

   A. Schlemmer, U. Parlitz, S. Luther, and 2 more authors

   Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Feb 2015

   Place: England

   Abs Link

   Transition patterns between different sleep stages are analysed in terms of probability distributions of symbolic sequences for young and old subjects with and without sleep disorder. Changes of these patterns due to ageing are compared with variations of transition probabilities due to sleep disorder.

2. Quantifying the causal strength of multivariate cardiovascular couplings with momentary information transfer.

   Jakob Runge, Maik Riedl, Andreas Müller, and 3 more authors

   Physiological measurement, Apr 2015

   Place: England

   Abs Link

   This article studies a recently introduced information-theoretic approach to detect and quantify the causal couplings in a complex cardiovascular system. In the first step a causal algorithm detects the coupling delays and in the second step the causal strength of each coupling mechanism is quantified using the recently introduced momentary information transfer. As an example, the method is applied to time series of respiration, systolic and diastolic blood pressure, and heart rate of pregnant healthy women and women suffering from pre-eclampsia. A possible explanation for the influence of heart rate on systolic blood pressure is found and some differences between healthy women and patients are discussed.

3. Heart rate detrended fluctuation indexes as estimate of obstructive sleep apnea severity.

   Eduardo Luiz Pereira Silva, Rafael Pereira, Luciano Neves Reis, and 4 more authors

   Medicine, Jan 2015

   Place: United States

   Abs Link

   In the present study, we aimed at investigating a heart rate variability (HRV) biomarker that could be associated with the severity of the apnea-hypopnea index (AHI), which could be used for an early diagnosis of obstructive sleep apnea (OSA). This was a cross-sectional observational study on 47 patients (age 36 ± 9.2 standard deviation) diagnosed with mild (23.4%), moderate (34%), or severe (42.6%) OSA. HRV was studied by linear measures of fast Fourier transform, nonlinear Poincaré analysis, and detrended fluctuation analysis (DFA)—DFA α1 characterizes short-term fluctuations, DFA α2 characterizes long-term fluctuations. Associations between polysomnography indexes (AHI, arousal index [AI], and oxygen desaturation index [ODI]) and HRV indexes were studied. Patients with different grades of AHI had similar sympathovagal balance levels as indicated by the frequency-domain and Poincaré HRV indexes. The DFA α2 index was significantly positive correlated with AHI, AI, and ODI (Pearson r: 0.55, 0.59, and 0.59, respectively, with P \textless 0.0001). The ROC analysis revealed that DFA α2 index predicted moderate and severe OSA with a sensitivity/specificity/area under the curve of 0.86/0.64/0.8 (P = 0.005) and 0.6/0.89/0.76 (P = 0.003), respectively. Our data indicate that the DFA α2 index may be used as a reliable index for the detection of OSA severity.

4. Beta blockers prevent correlation of plasma ACE2 activity with echocardiographic parameters in patients with idiopathic dilated cardiomyopathy.

   Yong Wang, Maria da Consolação V. Moreira, Silvia Heringer-Walther, and 4 more authors

   Journal of cardiovascular pharmacology, Jan 2015

   Place: United States

   Abs Link

   Plasma angiotensin-converting enzyme (ACE) 2 activity has been demonstrated to be an independent prognostic marker in Chagas’ disease, equally potent as B-type natriuretic peptide. This study aimed to investigate the prognostic potency of circulating ACE2 activity in patients with idiopathic dilated cardiomyopathy (DCM). Blood samples were withdrawn from patients with idiopathic DCM and healthy control subjects. The DCM patients were subdivided into 2 groups according to their New York Heart Association classification. The plasma ACE2 activity was measured by a fluorescence method. Plasma ACE2 activity was significantly increased in DCM patients, correlating with clinical severity. It was correlating with echocardiographic parameters in patients with DCM. Furthermore, plasma ACE2 activity had the potency to predict cardiac death and heart transplantation. However, compared with patients with Chagas’ disease, the correlation and predictive value of ACE2 activity in patients with DCM was much less pronounced. Beta blocker treatment in patients with DCM was identified to prevent the association between circulating ACE2 activity and echocardiographic parameters. Although ACE2 activity in blood samples of patients with DCM without beta blockers is potent in correlating with the severity of disease and in predicting death and heart transplantation, its correlation and prediction potency are significantly diminished by beta blocker treatment.

5. Enhancing dynamical signatures of complex systems through symbolic computation.

   Alberto Porta, Mathias Baumert, Dirk Cysarz, and 1 more author

   Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Feb 2015

   Place: England

   Link

2014

1. Cardio-respiratory coordination increases during sleep apnea.

   Maik Riedl, Andreas Müller, Jan F. Kraemer, and 3 more authors

   PloS one, Feb 2014

   Place: United States

   Abs Link

   Cardiovascular diseases are the main source of morbidity and mortality in the United States with costs of more than $170 billion. Repetitive respiratory disorders during sleep are assumed to be a major cause of these diseases. Therefore, the understanding of the cardio-respiratory regulation during these events is of high public interest. One of the governing mechanisms is the mutual influence of the cardiac and respiratory oscillations on their respective onsets, the cardio-respiratory coordination (CRC). We analyze this mechanism based on nocturnal measurements of 27 males suffering from obstructive sleep apnea syndrome. Here we find, by using an advanced analysis technique, the cardiogram, not only that the occurrence of CRC is significantly more frequent during respiratory sleep disturbances than in normal respiration (p-value\textless10(-51)) but also more frequent after these events (p-value\textless10(-15)). Especially, the latter finding contradicts the common assumption that spontaneous CRC can only be observed in epochs of relaxed conditions, while our newly discovered epochs of CRC after disturbances are characterized by high autonomic stress. Our findings on the connection between CRC and the appearance of sleep-disordered events require a substantial extension of the current understanding of obstructive sleep apneas and hypopneas.

2. Sleep apnea-hypopnea quantification by cardiovascular data analysis.

   Sabrina Camargo, Maik Riedl, Celia Anteneodo, and 3 more authors

   PloS one, Feb 2014

   Place: United States

   Abs Link

   Sleep disorders are a major risk factor for cardiovascular diseases. Sleep apnea is the most common sleep disturbance and its detection relies on a polysomnography, i.e., a combination of several medical examinations performed during a monitored sleep night. In order to detect occurrences of sleep apnea without the need of combined recordings, we focus our efforts on extracting a quantifier related to the events of sleep apnea from a cardiovascular time series, namely systolic blood pressure (SBP). Physiologic time series are generally highly nonstationary and entrap the application of conventional tools that require a stationary condition. In our study, data nonstationarities are uncovered by a segmentation procedure which splits the signal into stationary patches, providing local quantities such as mean and variance of the SBP signal in each stationary patch, as well as its duration L. We analysed the data of 26 apneic diagnosed individuals, divided into hypertensive and normotensive groups, and compared the results with those of a control group. From the segmentation procedure, we identified that the average duration \textlessL\textgreater, as well as the average variance \textlessσ2\textgreater, are correlated to the apnea-hypoapnea index (AHI), previously obtained by polysomnographic exams. Moreover, our results unveil an oscillatory pattern in apneic subjects, whose amplitude S* is also correlated with AHI. All these quantities allow to separate apneic individuals, with an accuracy of at least 79%. Therefore, they provide alternative criteria to detect sleep apnea based on a single time series, the systolic blood pressure.

3. Symbolic dynamics marker of heart rate variability combined with clinical variables enhance obstructive sleep apnea screening.

   A. G. Ravelo-García, P. Saavedra-Santana, G. Juliá-Serdá, and 6 more authors

   Chaos (Woodbury, N.Y.), Jun 2014

   Place: United States

   Abs Link

   Many sleep centres try to perform a reduced portable test in order to decrease the number of overnight polysomnographies that are expensive, time-consuming, and disturbing. With some limitations, heart rate variability (HRV) has been useful in this task. The aim of this investigation was to evaluate if inclusion of symbolic dynamics variables to a logistic regression model integrating clinical and physical variables, can improve the detection of subjects for further polysomnographies. To our knowledge, this is the first contribution that innovates in that strategy. A group of 133 patients has been referred to the sleep center for suspected sleep apnea. Clinical assessment of the patients consisted of a sleep related questionnaire and a physical examination. The clinical variables related to apnea and selected in the statistical model were age (p \textless 10(-3)), neck circumference (p \textless 10(-3)), score on a questionnaire scale intended to quantify daytime sleepiness (p \textless 10(-3)), and intensity of snoring (p \textless 10(-3)). The validation of this model demonstrated an increase in classification performance when a variable based on non-linear dynamics of HRV (p \textless 0.01) was used additionally to the other variables. For diagnostic rule based only on clinical and physical variables, the corresponding area under the receiver operating characteristic (ROC) curve was 0.907 (95% confidence interval (CI) = 0.848, 0.967), (sensitivity 87.10% and specificity 80%). For the model including the average of a symbolic dynamic variable, the area under the ROC curve was increased to 0.941 (95% = 0.897, 0.985), (sensitivity 88.71% and specificity 82.86%). In conclusion, symbolic dynamics, coupled with significant clinical and physical variables can help to prioritize polysomnographies in patients with a high probability of apnea. In addition, the processing of the HRV is a well established low cost and robust technique.

4. Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway.

   Robert Fischer, Anne Konkel, Heidrun Mehling, and 10 more authors

   Journal of lipid research, Jun 2014

   Place: United States

   Abs Link

   Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA) contribute to the regulation of cardiovascular function. CYP enzymes also accept EPA and DHA to yield more potent vasodilatory and potentially anti-arrhythmic metabolites, suggesting that the endogenous CYP-eicosanoid profile can be favorably shifted by dietary omega-3 fatty acids. To test this hypothesis, 20 healthy volunteers were treated with an EPA/DHA supplement and analyzed for concomitant changes in the circulatory and urinary levels of AA-, EPA-, and DHA-derived metabolites produced by the cyclooxygenase-, lipoxygenase (LOX)-, and CYP-dependent pathways. Raising the Omega-3 Index from about four to eight primarily resulted in a large increase of EPA-derived CYP-dependent epoxy-metabolites followed by increases of EPA- and DHA-derived LOX-dependent monohydroxy-metabolites including the precursors of the resolvin E and D families; resolvins themselves were not detected. The metabolite/precursor fatty acid ratios indicated that CYP epoxygenases metabolized EPA with an 8.6-fold higher efficiency and DHA with a 2.2-fold higher efficiency than AA. Effects on leukotriene, prostaglandin E, prostacyclin, and thromboxane formation remained rather weak. We propose that CYP-dependent epoxy-metabolites of EPA and DHA may function as mediators of the vasodilatory and cardioprotective effects of omega-3 fatty acids and could serve as biomarkers in clinical studies investigating the cardiovascular effects of EPA/DHA supplementation.

5. Robust fetal ECG extraction and detection from abdominal leads.

   Fernando Andreotti, Maik Riedl, Tilo Himmelsbach, and 7 more authors

   Physiological measurement, Aug 2014

   Place: England

   Abs Link

   The fetal ECG derived from abdominal leads provides an alternative to standard means of fetal monitoring. Furthermore, it permits long-term and ambulant recordings, which expands the range diagnostic possibilities for evaluating the fetal health state. However, due to the temporal and spectral overlap of maternal and fetal signals, the usage of abdominal leads imposes the need for elaborated signal processing routines.In this work a modular combination of processing techniques is presented. Its core consists of two maternal ECG estimation techniques, namely the extended Kalman smoother (EKS) and template adaption (TA) in combination with an innovative detection algorithm. Our detection method employs principles of evolutionary computing to detect fetal peaks by considering the periodicity and morphological characteristics of the fetal signal. In a postprocessing phase, single channel detections are combined by means of kernel density estimation and heart rate correction.The described methodology was presented during the Computing in Cardiology Challenge 2013. The entry was the winner of the closed-source events with average scores for events 4/5 with 15.1/3.32 (TA) and 69.5/4.58 (EKS) on training set-A and 20.4/4.57 (TA) and 219/7.69 (EKS) on test set-B, respectively. Using our own clinical data (24 subjects each 20 min recordings) and statistical measures beyond the Challenge’s scoring system, we further validated the proposed method. For our clinical data we obtained an average detection rate of 82.8% (TA) and 83.4% (EKS). The achieved results show that the proposed methods are able produce reliable fetal heart rate estimates from a restricted number of abdominal leads.

6. Cardiovascular variability before and after delivery: recovery from arterial stiffness in women with preeclampsia 4 days post partum.

   Thomas Walther, Andreas Voss, Mathias Baumert, and 5 more authors

   Hypertension in pregnancy, Feb 2014

   Place: England

   Abs Link

   OBJECTIVE: We studied the short-term response of autonomic control to delivery in normal pregnancies and pregnancies with preeclampsia (PE). METHODS: Fourteen healthy pregnant women and 13 women with PE were monitored within four days before and four days after delivery and compared to values of 14 non-pregnant women as controls using high-resolution electrocardiogram and noninvasive continuous blood pressure monitoring. RESULTS: In PE, blood pressure remained elevated four days postpartum, but markers for arterial stiffness normalized. In contrast, none of heart rate variability and baroreflex sensitivity parameters, altered due to either pregnancy or disease, were normalized 96 h after delivery. CONCLUSION: Four days after delivery, the maternal cardiovascular system is still strongly affected by pregnancy independent of the health status.

2013

1. Coupling analysis of transient cardiovascular dynamics.

   Andreas Müller, Maik Riedl, Thomas Penzel, and 3 more authors

   Biomedizinische Technik. Biomedical engineering, Apr 2013

   Place: Germany

   Abs Link

   The analysis of effects from coupling in and between systems is important in data-driven investigations as practiced in many scientific fields. It allows deeper insights into the mechanisms of interaction emerging among individual smaller systems when forming complex systems as in the human circulatory system. For systems featuring various regimes, usually only the epochs before and after a transition between different regimes are analyzed, although relevant information might be hidden within these transitions. Transient behavior of cardiovascular variables may emerge, on the one hand, from the recovery of the system after a severe disturbance or, on the other hand, from adaptive behavior throughout changes of states. It contains important information about the processes involved and the relations between state variables such as heart rate, blood pressure, and respiration. Therefore, we apply an ensemble approach to extend the method of symbolic coupling traces to time-variant coupling analysis. These new ensemble symbolic coupling traces are capable of determining coupling direction, strength, and time offset τ from transient dynamics in multivariate cardiovascular data. We use this method to analyze data recorded during an orthostatic test to reveal a transient structure that cannot be detected by classic methods.

2. Estimating coupling directions in the cardiorespiratory system using recurrence properties.

   Norbert Marwan, Yong Zou, Niels Wessel, and 2 more authors

   Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Aug 2013

   Place: England

   Abs Link

   The asymmetry of coupling between complex systems can be studied by conditional probabilities of recurrence, which can be estimated by joint recurrence plots. This approach is applied for the first time on experimental data: time series of the human cardiorespiratory system in order to investigate the couplings between heart rate, mean arterial blood pressure and respiration. We find that the respiratory system couples towards the heart rate, and the heart rate towards the mean arterial blood pressure. However, our analysis could not detect a clear coupling direction between the mean arterial blood pressure and respiration.

3. Diminished heart beat non-stationarities in congestive heart failure.

   Sabrina Camargo, Maik Riedl, Celia Anteneodo, and 2 more authors

   Frontiers in physiology, Aug 2013

   Place: Switzerland

   Abs Link

   Studies on heart rate variability (HRV) have become popular and the possibility of diagnosis based on non-invasive techniques compels us to overcome the difficulties originated on the environmental changes that can affect the signal. We perform a non-parametric segmentation which consists of locating the points where the signal can be split into stationary segments. By finding stationary segments we are able to analyze the size of these segments and evaluate how the signal changes from one segment to another, looking at the statistical moments given in each patch, for example, mean and variance. We analyze HRV data for 15 patients with congestive heart failure (CHF; 11 males, 4 females, age 56±11 years), 18 elderly healthy subjects (EH; 11 males, 7 females, age 50±7 years), and 15 young healthy subjects (YH; 11 females, 4 males, age 31±6 years). Our results confirm higher variance for YH, and EH, while CHF displays diminished variance with p-values \textless0.01, when compared to the healthy groups, presenting higher HRV in healthy subjects. Moreover, it is possible to distinguish between YH and EH with p \textless 0.05 through the segmentation outcomes. We found high correlations between the results of segmentation and standard measures of HRV analysis and a connection to results of detrended fluctuation analysis (DFA). The segmentation applied to HRV studies detects aging and pathological conditions effects on the non-stationary behavior of the analyzed groups, promising to contribute in complexity analysis and providing risk stratification measures.

4. TOCSY - Toolboxes for modelling of dynamical systems and time series.

   N. Wessel, N. Marwan, J. F. Krämer, and 1 more author

   Biomedizinische Technik. Biomedical engineering, Aug 2013

   Place: Germany

   Link
5. Different approaches of symbolic dynamics to quantify heart rate complexity.

   Dirk Cysarz, Alberto Porta, Nicola Montano, and 3 more authors

   Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference, Aug 2013

   Place: United States

   Abs Link

   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.

6. Classification of cardiovascular time series based on different coupling structures using recurrence networks analysis.

   Gonzalo Marcelo Ramírez Ávila, Andrej Gapelyuk, Norbert Marwan, and 4 more authors

   Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Aug 2013

   Place: England

   Abs Link

   We analyse cardiovascular time series with the aim of performing early prediction of preeclampsia (PE), a pregnancy-specific disorder causing maternal and foetal morbidity and mortality. The analysis is made using a novel approach, namely the ε-recurrence networks applied to a phase space constructed by means of the time series of the variabilities of the heart rate and the blood pressure (systolic and diastolic). All the possible coupling structures among these variables are considered for the analysis. Network measures such as average path length, mean coreness, global clustering coefficient and scale-local transitivity dimension are computed and constitute the parameters for the subsequent quadratic discriminant analysis. This allows us to predict PE with a sensitivity of 91.7 per cent and a specificity of 68.1 per cent, thus validating the use of this method for classifying healthy and preeclamptic patients.

7. Classifying healthy women and preeclamptic patients from cardiovascular data using recurrence and complex network methods.

   G. M. Ramírez Ávila, A. Gapelyuk, N. Marwan, and 4 more authors

   Autonomic neuroscience : basic & clinical, Nov 2013

   Place: Netherlands

   Abs Link

   It is urgently aimed in prenatal medicine to identify pregnancies, which develop life-threatening preeclampsia prior to the manifestation of the disease. Here, we use recurrence-based methods to distinguish such pregnancies already in the second trimester, using the following cardiovascular time series: the variability of heart rate and systolic and diastolic blood pressures. We perform recurrence quantification analysis (RQA), in addition to a novel approach, ε-recurrence networks, applied to a phase space constructed by means of these time series. We examine all possible coupling structures in a phase space constructed with the above-mentioned biosignals. Several measures including recurrence rate, determinism, laminarity, trapping time, and longest diagonal and vertical lines for the recurrence quantification analysis and average path length, mean coreness, global clustering coefficient, assortativity, and scale local transitivity dimension for the network measures are considered as parameters for our analysis. With these quantities, we perform a quadratic discriminant analysis that allows us to classify healthy pregnancies and upcoming preeclamptic patients with a sensitivity of 91.7% and a specificity of 45.8% in the case of RQA and 91.7% and 68% when using ε-recurrence networks, respectively.

8. Assessment of feature selection and classification approaches to enhance information from overnight oximetry in the context of apnea diagnosis.

   Daniel Alvarez, Roberto Hornero, J. Víctor Marcos, and 4 more authors

   International journal of neural systems, Oct 2013

   Place: Singapore

   Abs Link

   This study is aimed at assessing the usefulness of different feature selection and classification methodologies in the context of sleep apnea hypopnea syndrome (SAHS) detection. Feature extraction, selection and classification stages were applied to analyze blood oxygen saturation (SaO2) recordings in order to simplify polysomnography (PSG), the gold standard diagnostic methodology for SAHS. Statistical, spectral and nonlinear measures were computed to compose the initial feature set. Principal component analysis (PCA), forward stepwise feature selection (FSFS) and genetic algorithms (GAs) were applied to select feature subsets. Fisher’s linear discriminant (FLD), logistic regression (LR) and support vector machines (SVMs) were applied in the classification stage. Optimum classification algorithms from each combination of these feature selection and classification approaches were prospectively validated on datasets from two independent sleep units. FSFS + LR achieved the highest diagnostic performance using a small feature subset (4 features), reaching 83.2% accuracy in the validation set and 88.7% accuracy in the test set. Similarly, GAs + SVM also achieved high generalization capability using a small number of input features (7 features), with 84.2% accuracy on the validation set and 84.5% accuracy in the test set. Our results suggest that reduced subsets of complementary features (25% to 50% of total features) and classifiers with high generalization ability could provide high-performance screening tools in the context of SAHS.

9. Quantification of heart beat nonstationarities by nonparametric segmentation.

   Maik Riedl, Sabrina Camargo, Celia Anteneodo, and 2 more authors

   Biomedizinische Technik. Biomedical engineering, Aug 2013

   Place: Germany

   Link
10. Synchronisation and coupling analysis: applied cardiovascular physics in sleep medicine.

    Niels Wessel, Maik Riedl, Jan Kramer, and 3 more authors

    Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference, Aug 2013

    Place: United States

    Abs Link

    Sleep is a physiological process with an internal program of a number of well defined sleep stages and intermediate wakefulness periods. The sleep stages modulate the autonomous nervous system and thereby the sleep stages are accompanied by different regulation regimes for the cardiovascular and respiratory system. The differences in regulation can be distinguished by new techniques of cardiovascular physics. The number of patients suffering from sleep disorders increases unproportionally with the increase of the human population and aging, leading to very high expenses in the public health system. Therefore, the challenge of cardiovascular physics is to develop highly-sophisticated methods which are able to, on the one hand, supplement and replace expensive medical devices and, on the other hand, improve the medical diagnostics with decreasing the patient’s risk. Methods of cardiovascular physics are used to analyze heart rate, blood pressure and respiration to detect changes of the autonomous nervous system in different diseases. Data driven modeling analysis, synchronization and coupling analysis and their applications to biosignals in healthy subjects and patients with different sleep disorders are presented. Newly derived methods of cardiovascular physics can help to find indicators for these health risks.

2012

1. Computing complexity in cardiovascular oscillations: selected papers from the 6th Conference of the ESGCO.

   N. Wessel, and P. Leeuwen

   Computers in biology and medicine, Mar 2012

   Place: United States

   Link
2. Effects of awareness and nociception on heart rate variability during general anaesthesia.

   R. Huhle, M. Burghardt, S. Zaunseder, and 4 more authors

   Physiological measurement, Feb 2012

   Place: England

   Abs Link

   During anaesthesia awareness and nociception are serious complications that may further lead to haemodynamic instability. Specific monitoring of depth of hypnosis and depth of analgesia based on heart rate variability (HRV) analysis is eligible to improve patient safety and reduce efforts in post-operative care. Consequently, in this analysis we assess the applicability of HRV parameters during surgical interventions with standardized intravenous propofol-remifentanil-anaesthesia. Peri-operative electrocardiograms were recorded from cardiovascular stable patients (ASA Score I/II, N = 32, age: 36.4 ± 11.23 a, BMI: 25.2 ± 3.16) scheduled for trauma and dentofacial surgery. HRV time- and frequency-domain parameters, measures of complexity and nonlinear dynamics were compared by analysing longitudinally distributed 300 s intervals preceding/following induction of anaesthesia (BL-I1), intubation (I1-I2) and extubation (E1-E2). Mean value (meanNN) and standard deviation (sdNN) of the heart rate are influenced in BL-I1 (p \textless 0.001), I1-I2 (p \textless 0.05) and E1-E2 (p \textless 0.001). The number of forbidden words of symbolic dynamics changes significantly for BL-I1 (p \textless 0.001) and not for I1-I2 and E1-E2 (p \textgreater 0.05). Probability of low-variability POLVAR10 is significantly altered in all comparisons (BL-I1: Δ = 0.032, p \textless 0.01, I1-I2: Δ = 0.12, p \textless 0.05, E1-E2: Δ = 0.169, p \textless 0.01) but especially during nociception. While standard time-domain parameters lacked selectivity, parameters of symbolic dynamics appear to be specifically influenced by changes in depth of hypnosis and nociception, respectively. However, the lack of steady-state ventilation/breathing in this study needs to be considered in future research. To be used for clinical anaesthesia monitoring our results have to be prospectively validated in clinical studies.

3. Characterization of recombinant human C1 inhibitor secreted in milk of transgenic rabbits.

   Harrie A. Veen, Jaco Koiter, Carla J. M. Vogelezang, and 9 more authors

   Journal of biotechnology, Dec 2012

   Place: Netherlands

   Abs Link

   C1 inhibitor (C1INH) is a single-chain glycoprotein that inhibits activation of the contact system of coagulation and the complement system. C1INH isolated from human blood plasma (pd-hC1INH) is used for the management of hereditary angioedema (HAE), a disease caused by heterozygous deficiency of C1INH, and is a promise for treatment of ischemia-reperfusion injuries like acute myocardial or cerebral infarction. To obtain large quantities of C1INH, recombinant human C1INH (rhC1INH) was expressed in the milk of transgenic rabbits (12 g/l) harboring genomic human C1INH sequences fused to 5’ bovine αS(1) casein promoter sequences. Recombinant hC1INH was isolated from milk to a specific activity of 6.1 U/mg and a purity of 99%; by size-exclusion chromatography the 1% impurities consisted of multimers and N-terminal cleaved C1INH species. Mass spectrometric analysis of purified rhC1INH revealed a relative molecular mass (M(r)) of 67,200. Differences in M(r) on SDS PAGE and mass spectrometric analysis between rhC1INH and pd-hC1INH are explained by differential glycosylation (calculated carbohydrate contents of 21% and 28%, respectively), since protein sequencing analysis of rhC1INH revealed intact N- and C-termini. Host-related impurity analysis by ELISA revealed trace amounts of rabbit protein (approximately 10 ppm) in purified batches, but not endogenous rabbit C1INH. The kinetics of inhibition of the target proteases C1s, Factor XIIa, kallikrein and Factor XIa by rhC1INH and pd-hC1INH, indicated comparable inhibitory potency and specificity. Recently, rhC1INH (Ruconest(®)) has been approved by the European Medicines Agency for the treatment of acute attacks of HAE.

4. Classifying cardiac biosignals using ordinal pattern statistics and symbolic dynamics.

   U. Parlitz, S. Berg, S. Luther, and 3 more authors

   Computers in biology and medicine, Mar 2012

   Place: United States

   Abs Link

   The performance of (bio-)signal classification strongly depends on the choice of suitable features (also called parameters or biomarkers). In this article we evaluate the discriminative power of ordinal pattern statistics and symbolic dynamics in comparison with established heart rate variability parameters applied to beat-to-beat intervals. As an illustrative example we distinguish patients suffering from congestive heart failure from a (healthy) control group using beat-to-beat time series. We assess the discriminative power of individual features as well as pairs of features. These comparisons show that ordinal patterns sampled with an additional time lag are promising features for efficient classification.

5. Effect of CPAP therapy on daytime cardiovascular regulations in patients with obstructive sleep apnea.

   T. Penzel, M. Riedl, A. Gapelyuk, and 8 more authors

   Computers in biology and medicine, Mar 2012

   Place: United States

   Abs Link

   Obstructive sleep apnea (OSA) is a sleep disorder with a high prevalence that causes pathological changes in cardiovascular regulation during the night and also during daytime. We investigated whether the treatment of OSA at night by means of continuous positive airway pressure (CPAP) improves the daytime consequences. Twenty-eight patients with OSA, 18 with arterial hypertension, 10 with normal blood pressure, were investigated at baseline and with three months of CPAP treatment. Ten age and sex matched healthy control subjects were investigated for comparisons. We recorded a resting period with 20min quiet breathing and an exercise stress test during daytime with ECG and blood pressure (Portapres). The bicycle ergometry showed a significant reduction of the diastolic blood pressure at a work load of 50W and 100W (p\textless0.05 and p\textless0.01, respectively) and a decrease of the heart rate recovery time after the stress test (p\textless0.05). These results indicate a reduction of vascular resistance and sympathetic activity during daytime. The coupling analysis of the resting periods by means of symbolic coupling traces approach indicated an effect of the CPAP therapy on the baroreflex reaction in hypertensive patients where influences of the systolic blood pressure on the heart rate changed from pathological patterns to adaptive mechanisms of the normotensive patients (p\textless0.05).

6. Prognostic significance of circulating levels of hepatocyte growth factor in patients with chagas’ disease and idiopathic dilated cardiomyopathy.

   Yong Wang, Maria da Consolação V. Moreira, Adnan Khan, and 5 more authors

   Cardiology, Mar 2012

   Place: Switzerland

   Abs Link

   OBJECTIVES: Hepatocyte growth factor (HGF) plays an important role in the improvement in cardiac function and remodeling in a variety of cardiovascular diseases. It is also a strong predictor of mortality in some heart failure (HF) patients. However, its prognostic value in patients with Chagas’ disease (CD) or idiopathic dilated cardiomyopathy (DCM) remains to be investigated. METHODS AND RESULTS: In this prospective cohort study, HGF concentrations were measured in patients with CD (n = 91), DCM (n = 47), and control subjects (n = 25). While no difference was detected for patients with New York Heart Association class I-II, HGF was significantly increased in advanced HF patients (New York Heart Association class III-IV) in both CD and DCM groups, compared with healthy subjects. There was a strong correlation between HGF and left ventricular ejection fraction in CD patients. However, there was no correlation in patients with DCM. Despite its strong correlation with left ventricular ejection fraction in CD patients, HGF failed to predict mortality and necessity for heart transplant in both CD and DCM patients. CONCLUSIONS: Although HGF can be significantly increased in advanced HF patients with CD and DCM, its prognostic value for endpoints is minor. Therefore, the formerly described predictive power for HGF in HF might be restricted to specific etiologies of HF.

7. Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG.

   Lingyi Lu, Geraldine Cancel-Tassin, Antoine Valeri, and 55 more authors

   The Prostate, Mar 2012

   Place: United States

   Abs Link

   BACKGROUND: In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 PC families, we identified suggestive evidence for linkage (i.e., LOD ≥ 1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members. METHODS: In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 International Consortium for Prostate Cancer Genetics (ICPCG) groups. RESULTS: Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37 cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD scores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology. CONCLUSIONS: These results will be useful in prioritizing future susceptibility gene discovery efforts in this common cancer.

8. Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families.

   Joan E. Bailey-Wilson, Erica J. Childs, Cheryl D. Cropp, and 49 more authors

   BMC medical genetics, Jun 2012

   Place: England

   Abs Link

   BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.

2011

1. Biosignal 2010: Advanced technologies in intensive care and sleep medicine.

   Niels Wessel, Jürgen Kurths, Hagen Malberg, and 1 more author

   Physiological measurement, Nov 2011

   Place: England

   Link
2. Preserved autonomic regulation in patients undergoing transcatheter aortic valve implantation (TAVI): a prospective, comparative study.

   Beatrice Retzlaff, Niels Wessel, Maik Riedl, and 6 more authors

   Biomedizinische Technik. Biomedical engineering, Aug 2011

   Place: Germany

   Abs Link

   Heart rate and blood pressure variability as well as baroreflex sensitivity (BRS) lead to additional insights on the patients’ prognosis after cardiovascular events. The following study was performed to assess the differences in the postoperative recovery of the autonomic regulation after transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). Fifty-eight consecutive patients were enrolled in a prospective study; 24 underwent TAVI and 34 SAVR. BRS was calculated according to the Dual Sequence Method, heart rate variability (HRV) was evaluated using standard linear as well as nonlinear parameters. HRV and BRS parameters were reduced after surgery in patients with SAVR only (meanNN: p\textless0.001, sdNN: p\textless0.05, Shannon: p\textless0.01, BRS: p\textless0.01), while these indexes were preserved in patients after TAVI. Simultaneously, an increased complexity of blood pressure (BP) in SAVR patients (fwShannon: p\textless0.001, fwRenyi4: p\textless0.001), but not in TAVI patients was recorded. In this study we were able to demonstrate for the first time that, in contrast to patients undergoing conventional open surgery, there are fewer alterations of the cardiovascular autonomic system in patients with TAVI.

3. Symbolic coupling traces for causality analysis of cardiovascular control.

   N. Wessel, A. Suhrbier, M. Riedl, and 5 more authors

   Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference, Aug 2011

   Place: United States

   Abs Link

   Directional coupling analysis of time series is an important subject of current research. In this paper, a method based on symbolic dynamics for the detection of time-delayed coupling in biosignals is presented. The symbolic coupling traces, defined as the symmetric and diametric traces of the bivariate word distribution, allow for a more reliable quantification of coupling and are compared with established methods like mutual information and cross recurrence analysis. The symbolic coupling traces method is applied to appropriate model systems and cardiological data which demonstrate its advantages especially for nonstationary and noisy data. Moreover, the method of symbolic coupling traces is used to analyze and quantify time-delayed coupling of cardiovascular measurements during different sleep stages. Significant different regulatory mechanisms are detected not only between the deep sleep and the other sleep stages but also between healthy subjects and patients. The proposed method may help to indicate pathological changes in cardiovascular regulation and also effects of continuous positive airway pressure therapy on the cardiovascular system.

4. Does the aminopeptidase A have prognostic and diagnostic value in Chagas disease and other dilated cardiomyopathies?

   Yong Wang, Maria da Consolação V. Moreira, Silvia Heringer-Walther, and 5 more authors

   Journal of cardiovascular pharmacology, Oct 2011

   Place: United States

   Abs Link

   Chagas disease (CD), which is caused by the protozoan Trypanosoma cruzi, is a major cause of heart failure in Latin America. We investigated if plasma activity of one of the enzymes being part of the renin-angiotensin system, aminopeptidase A (APA), has diagnostic and prognostic potency in patients with CD and dilated cardiomyopathies (DCMs) due to other causes. Blood samples were taken from 94 patients with CD, 46 patients with DCM, and 34 healthy control subjects. Plasma APA activity was determined by fluorometry assays. The average follow-up time was 39 months; by the end of study, 33 patients had died and another 13 received heart transplant. There was no significant alteration in plasma APA activity in the patients with CD or DCM, as compared with that in controls. The Pearson correlation of echocardiographic data with plasma APA activity in patients with CD and DCM did not reveal any significant correlation with left-ventricular ejection fraction or other echocardiographic parameters. APA activity was unable to predict mortality or the need for heart transplant. Detection of APA activity in plasma may not prove suitable for prognosis in patients with heart failure and is unable to screen or diagnose asymptomatic patients with CD for early therapy.

5. Cardiovascular and respiratory regulation during sleep in patients with sleep apnea with and without hypertension.

   Thomas Penzel, Alexander Suhrbier, G. Bretthauer, and 5 more authors

   Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference, Oct 2011

   Place: United States

   Abs Link

   Sleep is a physiological process with an internal program of a number of well defined sleep stages and intermediate wakefulness periods. The sleep stages do modulate the autonomous nervous system and thereby the sleep stages are accompanied by different regulation regimes for the cardiovascular and respiratory system. The differences in regulation can be distinguished by new analysis techniques on the recorded signals. In addition to normal sleep regulation some sleep disorders affect the cardiovascular and respiratory regulation. The most prevalent disorder linked to sleep and changes in the autonomous system is obstructive sleep apnea. In patients with obstructive sleep apnea marked short term changes in cardiovascular and respiratory regulation are observed during sleep. These abnormalities in regulation are further differentiated between the sleep stages. For long term changes obstructive sleep apnea is recognized as a major risk factor for arterial hypertension. Treatment of obstructive sleep apnea lowers blood pressure during the night and over time also lowers blood pressure during daytime. In this study we investigated 18 patients with sleep apnea and normal blood pressure, 10 patients with sleep apnea and arterial hypertension and 10 normal subjects as controls. Both patient groups were tested with cardiorespiratory polysomnography before and under CPAP therapy. The effects on cardiovascular and respiratory regulation during sleep and daytime are investigated in the three groups.

6. Cardiovascular regulation in different sleep stages in the obstructive sleep apnea syndrome.

   Andrej Gapelyuk, Maik Riedl, Alexander Suhrbier, and 6 more authors

   Biomedizinische Technik. Biomedical engineering, Aug 2011

   Place: Germany

   Abs Link

   Heart rate and blood pressure variability analysis as well as baroreflex sensitivity have been proven to be powerful tools for the assessment of autonomic control in clinical practice. Their ability to detect systematic changes caused by different states, diseases and treatments shall be shown for sleep disorders. Therefore, we consider 18 normotensive and 10 hypertensive patients suffering from obstructive sleep apnea syndrome (OSAS) before and after a three-month continuous positive airway pressure (CPAP) therapy. Additionally, an age and sex matched control group of 10 healthy subjects is examined. Linear and nonlinear parameters of heart rate and blood pressure fluctuation as well as the baroreflex sensitivity are used to answer the question whether there are differences in cardiovascular regulation between the different sleep stages and groups. Moreover, the therapeutic effect of CPAP therapy in OSAS patients shall be investigated. Kruskal-Wallis tests between the sleep stages for each group show significant differences in the very low spectral component of heart rate (VLF/P: 0.0033-0.04 Hz, p\textless0.01) which indicates differences in metabolic activity during the night. Furthermore, the decrease of Shannon entropy of word distribution as a parameter of systolic blood pressure during non-REM sleep reflects the local dominance of the vagal system (p\textless0.05). The increased sympathetic activation of the patients leads to clear differences of cardiovascular regulation in different sleep stages between controls and patients. We found a significant reduction of baroreflex sensitivity in slow wave sleep in the OSAS patients (Mann-Whitney test, p\textless0.05) compared to controls, which disappeared after three months of CPAP therapy. Hence, our results demonstrate the ability of cardiovascular analyzes to separate between healthy and pathological regulation as well as between different severities of OSAS in this retrospective study.

7. Efficacy and safety of short-term genistein intervention in patients with localized prostate cancer prior to radical prostatectomy: a randomized, placebo-controlled, double-blind Phase 2 clinical trial.

   Bato Lazarevic, Gro Boezelijn, Lien My Diep, and 13 more authors

   Nutrition and cancer, Aug 2011

   Place: United States

   Abs Link

   We conducted a placebo-controlled, block-randomized double-blind Phase 2 study to examine the effect of 30 mg synthetic genistein daily on serum and tissue biomarkers in patients with localized prostate cancer (CaP). Fifty-four study subjects were recruited and randomized to treatment with genistein (n = 23) or placebo (n = 24) for 3 to 6 wk prior to prostatectomy. Seven study subjects were noncompliant to the study protocol. Adverse events were few and mild. Serum prostate specific antigen (PSA) decreased by 7.8% in the genistein arm and increased by 4.4% in the placebo arm (P = 0.051). The PSA level was reduced in tumor tissue compared to normal tissue in the placebo arm. In the genistein arm, the PSA level in tumor and normal tissue was comparable. Total cholesterol was significantly lower in the genistein arm (P = 0.013). There were no significant effects on thyroid or sex hormones. Plasma concentrations of total genistein were on average 100-fold higher in the genistein arm after treatment (P \textless 0.001). Genistein at a dose that can be easily obtained from a diet rich in soy reduced the level of serum PSA in patients with localized CaP, without any effects on hormones. It was well tolerated and had a beneficial effect on blood cholesterol.

2010

1. Amino-terminal fragment of C-type natriuretic peptide precursor and C-type natriuretic peptide do not correlate in patients with Chagas disease: role for neutral endopeptidase.

   Yong Wang, Maria da Consolação V. Moreira, Silvia Heringer-Walther, and 4 more authors

   Journal of cardiovascular pharmacology, Jan 2010

   Place: United States

   Abs Link

   Atrial and B-type natriuretic peptides (ANP and BNP), but not C-type natriuretic peptide (CNP), have been identified to be diagnostic and prognostic markers in Chagas disease (CD). Although ANP and BNP excessively rise in patients with CD, increase in CNP is just minor. Our study aimed to investigate the mechanisms leading to CNP insensitivity to heart failure (HF) stimuli. Amino-terminal fragment of CNP precursor (NT-proCNP) and activity of neutral endopeptidase (NEP) were quantified to monitor CNP generation and degradation, respectively. Blood samples were collected from patients with CD and control healthy subjects. NT-proCNP concentrations were significantly lower in patients with CD without systolic dysfunction compared with healthy subjects. Despite a trend toward increase with rising heart failure clinical severity, it was significantly correlated with left ventricular ejection fraction and other echocardiographic parameters. As shown for CNP before, NT-proCNP could not predict mortality and heart transplant. Importantly, it had no statistical correlation with CNP. Additionally, NEP activity was significantly increased in New York Heart Association III and IV patients with HF but was positively correlated with CNP concentration. Our data demonstrates that generation of CNP is not enhanced under HF condition like CD. Thus, CNP rise by severe HF is caused by its less degradation that is independent of NEP activity.

2. Short-term couplings of the cardiovascular system in pregnant women suffering from pre-eclampsia.

   Maik Riedl, Alexander Suhrbier, Holger Stepan, and 2 more authors

   Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, May 2010

   Place: England

   Abs Link

   Pre-eclampsia (PE), a serious pregnancy-specific disorder, causes significant neonatal and maternal morbidity and mortality. Recent studies showed that cardiovascular variability parameters as well as the baroreflex sensitivity remarkably improve its early diagnosis. For a better understanding of the dynamical changes caused by PE, in this study the coupling between respiration, systolic and diastolic blood pressure, and heart rate is investigated. Thirteen datasets of healthy pregnant women and 10 of subjects suffering from PE are included. Nonlinear additive autoregressive models with external input are used for a model-based coupling analysis following the idea of Granger causality. To overcome the problem of misdetections of standard methods in systems with a dominant driver, a heuristic ensemble approach is used here. A coupling is assumed to be real when existent in more than 80 per cent of the ensemble members, and otherwise denoted as artefacts. As the main result, we found that the coupling structure between heart rate, systolic blood pressure, diastolic blood pressure and respiration for healthy subjects and PE patients is the same and reliable. As a pathological mechanism, however, a significant increased respiratory influence on the diastolic blood pressure could be found for PE patients (p=0.003). Moreover, the nonlinear form of the respiratory influence on the heart rate is significantly different between the two groups (p=0.002). Interestingly, the influence of systolic blood pressure on the heart rate is not selected, which indicates that the baroreflex sensitivity estimation strongly demands the consideration of causal relationships between heart rate, blood pressure and respiration. Finally, our results point to a potential role of respiration for understanding the pathogenesis of PE.

3. Cardiovascular regulation during sleep quantified by symbolic coupling traces.

   A. Suhrbier, M. Riedl, H. Malberg, and 4 more authors

   Chaos (Woodbury, N.Y.), Dec 2010

   Place: United States

   Abs Link

   Sleep is a complex regulated process with short periods of wakefulness and different sleep stages. These sleep stages modulate autonomous functions such as blood pressure and heart rate. The method of symbolic coupling traces (SCT) is used to analyze and quantify time-delayed coupling of these measurements during different sleep stages. The symbolic coupling traces, defined as the symmetric and diametric traces of the bivariate word distribution matrix, allow the quantification of time-delayed coupling. In this paper, the method is applied to heart rate and systolic blood pressure time series during different sleep stages for healthy controls as well as for normotensive and hypertensive patients with sleep apneas. Using the SCT, significant different cardiovascular mechanisms not only between the deep sleep and the other sleep stages but also between healthy subjects and patients can be revealed. The SCT method is applied to model systems, compared with established methods, such as cross correlation, mutual information, and cross recurrence analysis and demonstrates its advantages especially for nonstationary physiological data. As a result, SCT proves to be more specific in detecting delays of directional interactions than standard coupling analysis methods and yields additional information which cannot be measured by standard parameters of heart rate and blood pressure variability. The proposed method may help to indicate the pathological changes in cardiovascular regulation and also the effects of continuous positive airway pressure therapy on the cardiovascular system.

4. Plasma ACE2 activity is an independent prognostic marker in Chagas’ disease and equally potent as BNP.

   Yong Wang, Maria da Consolação V. Moreira, Silvia Heringer-Walther, and 5 more authors

   Journal of cardiac failure, Feb 2010

   Place: United States

   Abs Link

   BACKGROUND: Angiotensin-converting enzyme (ACE) 2 is a novel homologue of ACE. It metabolizes angiotensin (Ang)II to Ang-(1-7). This study aims to investigate the diagnostic and prognostic potency of circulating ACE2 activity in patients with heart failure (HF) from Chagas’ disease (CD). METHODS AND RESULTS: Blood samples were obtained from 111 CD patients and 40 age- and gender-matched healthy subjects. The CD patients were further subdivided according to their New York Heart Association classification. ACE2 activity was significantly increased in CD patients with HF, but not in patients without systolic dysfunction. Moreover, plasma ACE2 activity was significantly correlated with their clinical severity and echocardiographic parameters. Importantly, the potency of circulating ACE2 activity in CD patients was equally potent as that of B-type natriuretic peptide to predict cardiac death and heart transplant. Most importantly, patients with both parameters elevated were on a 5-fold higher risk to reach an endpoint than patients with increase in only 1 of the 2 parameters. CONCLUSIONS: Determination of ACE2 activity may provide a new and important diagnostic and prognostic marker for patients with CD. ACE2 activity and BNP concentration have additive predictive value and may be used in combination to offer a new dimension of prediction in HF.

5. Cardiac magnetic field mapping quantified by Kullback-Leibler entropy detects patients with coronary artery disease.

   A. Gapelyuk, A. Schirdewan, R. Fischer, and 1 more author

   Physiological measurement, Oct 2010

   Place: England

   Abs Link

   Cardiac magnetic field mapping (CMFM) is a noninvasive method to determine cardiac electrical activity. We analysed the utility of CMFM for the detection of patients with coronary artery disease (CAD) without subjecting them to stress. We studied 59 healthy control subjects and 101 patients with CAD without previous myocardial infarction (MI). The heart’s magnetic field was recorded over the anterior chest wall using a multichannel magnetic measurement system with axial second-order gradiometers. The evaluation of CMFM was based on comparison of the ’ideal’ group mean maps of young healthy subjects and maps of examined individuals. Three measures of similarity were considered: Kullback-Leibler (KL) entropy, normalized residual magnetic field strength and deviations in the magnetic field map orientation. The mean values of these parameters during the depolarization and repolarization were used for further classification with the help of logistic regression. The feature set based on the KL-entropy demonstrated the best classification results (sensitivity/specificity of 85/80%), followed by the residual feature (85/75%) and the magnetic field orientation feature (80/73%) sets. The forward stepwise technique was applied to select the best set of features from the combined feature set. Two parameters were selected, namely the KL-entropy for the repolarization period and the residual parameter for the depolarization period. The classification based on these parameters demonstrated a sensitivity of 88% and a specificity of 88% for the distinction of CAD patients from the control subjects. The area under the receiver operator curve was 94%. Hence, we suggest that CMFM evaluation based on KL-entropy is a promising technique to identify patients with CAD.

6. Investigation of an automatic sleep stage classification by means of multiscorer hypnogram.

   V. C. Figueroa Helland, A. Gapelyuk, A. Suhrbier, and 4 more authors

   Methods of information in medicine, Oct 2010

   Place: Germany

   Abs Link

   OBJECTIVES: Scoring sleep visually based on polysomnography is an important but time-consuming element of sleep medicine. Whereas computer software assists human experts in the assignment of sleep stages to polysomnogram epochs, their performance is usually insufficient. This study evaluates the possibility to fully automatize sleep staging considering the reliability of the sleep stages available from human expert sleep scorers. METHODS: We obtain features from EEG, ECG and respiratory signals of polysomnograms from ten healthy subjects. Using the sleep stages provided by three human experts, we evaluate the performance of linear discriminant analysis on the entire polysomnogram and only on epochs where the three experts agree in their sleep stage scoring. RESULTS: We show that in polysomnogram intervals, to which all three scorers assign the same sleep stage, our algorithm achieves 90% accuracy. This high rate of agreement with the human experts is accomplished with only a small set of three frequency features from the EEG. We increase the performance to 93% by including ECG and respiration features. In contrast, on intervals of ambiguous sleep stage, the sleep stage classification obtained from our algorithm, agrees with the human consensus scorer in approximately 61%. CONCLUSIONS: These findings suggest that machine classification is highly consistent with human sleep staging and that error in the algorithm’s assignments is rather a problem of lack of well-defined criteria for human experts to judge certain polysomnogram epochs than an insufficiency of computational procedures.

7. Cardiovascular and respiratory dynamics in patients with sleep apnea.

   Thomas Penzel, Niels Wessel, Maik Riedl, and 3 more authors

   Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference, Oct 2010

   Place: United States

   Abs Link

   Sleep is an active and regulated process with restorative functions for physical and mental conditions. Based on recordings of brain waves and the analysis of characteristic patterns and waveforms it is possible to distinguish wakefulness and five sleep stages. Sleep and the sleep stages modulate autonomous nervous system functions such as body temperature, respiration, blood pressure, and heart rate. Methods of statistical physics are used to analyze heart rate and respiration to detect changes of the autonomous nervous system during sleep. Detrended fluctuation analysis and synchronization analysis and their applications to heart rate and respiration during sleep in healthy subjects and patients with sleep disorders are presented. The observed changes can be used to distinguish sleep stages in healthy subjects as well as to differentiate normal and disturbed sleep on the basis of heart rate and respiration recordings without direct recording of brain waves. Of special interest are the cardiovascular consequences of disturbed sleep because they present a risk factor for cardiovascular disorders such as arterial hypertension, cardiac ischemia, sudden cardiac death, and stroke.

2009

1. Addressing the complexity of cardiovascular regulation.

   Alberto Porta, Marco Di Rienzo, Niels Wessel, and 1 more author

   Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Apr 2009

   Place: England

   Link
2. Testing foetal-maternal heart rate synchronization via model-based analyses.

   Maik Riedl, Peter Leeuwen, Alexander Suhrbier, and 4 more authors

   Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Apr 2009

   Place: England

   Abs Link

   The investigation of foetal reaction to internal and external conditions and stimuli is an important tool in the characterization of the developing neural integration of the foetus. An interesting example of this is the study of the interrelationship between the foetal and the maternal heart rate. Recent studies have shown a certain likelihood of occasional heart rate synchronization between mother and foetus. In the case of respiratory-induced heart rate changes, the comparison with maternal surrogates suggests that the evidence for detected synchronization is largely statistical and does not result from physiological interaction. Rather, they simply reflect a stochastic, temporary stability of two independent oscillators with time-variant frequencies. We reanalysed three datasets from that study for a more local consideration. Epochs of assumed synchronization associated with short-term regulation of the foetal heart rate were selected and compared with synchronization resulting from white noise instead of the foetal signal. Using data-driven modelling analysis, it was possible to identify the consistent influence of the heartbeat duration of maternal beats preceding the foetal beats during epochs of synchronization. These maternal beats occurred approximately one maternal respiratory cycle prior to the affected foetal beat. A similar effect could not be found in the epochs without synchronization. Simulations based on the fitted models led to a higher likelihood of synchronization in the data segments with assumed foetal-maternal interaction than in the segment without such assumed interaction. We conclude that the data-driven model-based analysis can be a useful tool for the identification of synchronization.

3. Prognostic value of natriuretic peptides in Chagas’ disease: a head-to-head comparison of the 3 natriuretic peptides.

   Maria da Consolação V. Moreira, Yong Wang, Silvia Heringer-Walther, and 2 more authors

   Congestive heart failure (Greenwich, Conn.), Apr 2009

   Place: United States

   Abs Link

   To determine the diagnostic and prognostic value of natriuretic peptides in patients with Chagas’ disease (CD), the authors first measured atrial (ANP), B-type (BNP), and C-type natriuretic peptide (CNP) and compared their diagnostic and prognostic capacity with that in other dilated cardiomyopathies (DCM). The CD and DCM patients were subdivided according to their New York Heart Association (NYHA) classification. Circulating ANP and more pronounced BNP, but not CNP, were increased in CD and DCM patients in relation to NYHA class. Importantly, ANP and BNP were already significantly elevated in CD patients without systolic ventricular dysfunction. All 3 natriuretic peptides were correlated with echocardiographic parameters in CD patients. While ANP and BNP have high predictive value for mortality and necessity for heart transplant in CD, CNP can not predict them. Thus, ANP and BNP rather than CNP could be used as valuable molecular markers to identify asymptomatic CD patients for early therapy and predict clinical outcomes.

4. Is the normal heart rate "chaotic" due to respiration?

   Niels Wessel, Maik Riedl, and Jürgen Kurths

   Chaos (Woodbury, N.Y.), Jun 2009

   Place: United States

   Abs Link

   The incidence of cardiovascular diseases increases with the growth of the human population and an aging society, leading to very high expenses in the public health system. Therefore, it is challenging to develop sophisticated methods in order to improve medical diagnostics. The question whether the normal heart rate is chaotic or not is an attempt to elucidate the underlying mechanisms of cardiovascular dynamics and therefore a highly controversial topical challenge. In this contribution we demonstrate that linear and nonlinear parameters allow us to separate completely the data sets of the three groups provided for this controversial topic in nonlinear dynamics. The question whether these time series are chaotic or not cannot be answered satisfactorily without investigating the underlying mechanisms leading to them. We give an example of the dominant influence of respiration on heart beat dynamics, which shows that observed fluctuations can be mostly explained by respiratory modulations of heart rate and blood pressure (coefficient of determination: 96%). Therefore, we recommend reformulating the following initial question: "Is the normal heart rate chaotic?" We rather ask the following: "Is the normal heart rate ’chaotic’ due to respiration?"

5. Influence of paced maternal breathing on fetal-maternal heart rate coordination.

   P. Van Leeuwen, D. Geue, M. Thiel, and 6 more authors

   Proceedings of the National Academy of Sciences of the United States of America, Aug 2009

   Place: United States

   Abs Link

   Pregnant mothers often report a special awareness of and bonding with their unborn child. Little is known about this relationship although it may offer potential for the assessment of the fetal condition. Recently we found evidence of short epochs of fetal-maternal heart rate synchronization under uncontrolled conditions with spontaneous maternal breathing. Here, we examine whether the occurrence of such epochs can be influenced by maternal respiratory arrhythmia induced by paced breathing at several different rates (10, 12, 15, and 20 cycles per minute). To test for such weak and nonstationary synchronizations among the fetal-maternal subsystems, we apply a multivariate synchronization analysis technique and test statistics based on twin surrogates. We find a clear increase in synchronization epochs mostly at high maternal respiratory rates in the original but not in the surrogate data. On the other hand, fewer epochs are found at low respiratory rates both in original and surrogate data. The results suggest that the fetal cardiac system seems to possess the capability to adjust its rate of activation in response to external–i.e., maternal–stimulation. Hence, the pregnant mothers’ special awareness to the unborn child may also be reflected by fetal-maternal interaction of cardiac activity. Our approach opens up the chance to examine this interaction between independent but closely linked physiological systems.

6. Depression of cardiovascular autonomic function is more pronounced after mitral valve surgery: evidence for direct trauma.

   Beatrice Retzlaff, Robert Bauernschmitt, Hagen Malberg, and 6 more authors

   Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Apr 2009

   Place: England

   Abs Link

   The analysis of baroreflex sensitivity (BRS) and heart rate variability (HRV) leads to additional insights into patients’ prognosis after cardiovascular events. The following study was performed to assess the differences in the post-operative recovery of autonomic regulation after mitral valve (MV) and aortic valve (AV) surgery with a heart-lung machine. Among the 43 consecutive male patients enrolled in a prospective study, 26 underwent isolated AV surgery and 17 isolated MV surgery. Blood pressure as well as ECG signals were recorded the day before, 24 hours after and one week after surgery. BRS was calculated according to the dual sequence method, and HRV was calculated using standard linear as well as nonlinear parameters. There were no major differences between the two groups in the pre-operative values. At 24 hours a comparable depression of HRV and BRS in both groups was observed, while at 7 days there was partial recovery in AV patients, which was absent in MV patients: p(AV versus MV)\textless0.001. While the response of the autonomic system to surgery is similar in AV and MV patients, there is obviously a decreased ability to recover in MV patients, probably attributed to traumatic lesions of the autonomic nervous system by opening the atria. Ongoing research is required for further clarification of the pathophysiology of this phenomenon and to establish strategies to restore autonomic function.

2008

1. Prognostic value of natriuretic peptides in Chagas’ disease: a 3-year follow-up investigation.

   Maria da Consolação V. Moreira, Silvia Heringer-Walther, Niels Wessel, and 4 more authors

   Cardiology, Apr 2008

   Place: Switzerland

   Abs Link

   BACKGROUND: Chagas’ disease (CD) affects around 18 million people in Latin America. To determine the diagnostic and prognostic value of natriuretic peptides in patients with CD, we measured atrial (ANP) and brain natriuretic peptide (BNP), and compared the findings with other dilated cardiomyopathies (DCM). METHODS: Blood samples were obtained from 111 CD patients, 62 patients with DCM due to other causes, and 43 gender- and age-matched healthy subjects. The CD and DCM patients were subdivided according to their NYHA classification. Natriuretic peptide concentrations were determined by immunoradiometric assays. RESULTS: ANP and more pronounced BNP levels were increased in CD and DCM patients in relation to the NYHA class. Circulating BNP concentrations were higher in CD patients in NYHA classes I-II than in the corresponding DCM patients (p = 0.020). Importantly, ANP and BNP were already significantly elevated in CD patients without systolic ventricular dysfunction (p \textless or = 0.001). In CD patients, both peptides were highly correlated with echocardiographic parameters (p \textless 10(-14)). Both ANP and BNP had comparable ability to predict death or the necessity for heart transplant (p \textless 0.0001). CONCLUSION: Natriuretic peptide levels can be used as a marker of asymptomatic CD without ventricular dysfunction and thus could be an ideal tool to identify these patients for early therapy.

2. Ventricular arrhythmias and changes in heart rate preceding ventricular tachycardia in patients with an implantable cardioverter defibrillator.

   Claudia Lerma, Niels Wessel, Alexander Schirdewan, and 2 more authors

   Medical & biological engineering & computing, Jul 2008

   Place: United States

   Abs Link

   The objective was to determine the characteristics of heart rate variability and ventricular arrhythmias prior to the onset of ventricular tachycardia (VT) in patients with an implantable cardioverter defibrillator (ICD). Sixty-eight beat-to-beat time series from 13 patients with an ICD were analyzed to quantify heart rate variability and ventricular arrhythmias. The episodes of VT were classified in one of two groups depending on whether the sinus rate in the 1 min preceding the VT was greater or less than 90 beats per minute. In a subset of patients, increased heart rate and reduced heart rate variability was often observed up to 20 min prior to the VT. There was a non-significant trend to higher incidence of premature ventricular complexes (PVCs) before VT compared to control recordings. The patterns of the ventricular arrhythmias were highly heterogeneous among different patients and even within the same patient. Analysis of the changes of heart rate and heart rate variability may have predictive value about the onset of VT in selected patients. The patterns of ventricular arrhythmia could not be used to predict onset of VT in this group of patients.

3. Modeling the cardiovascular system using a nonlinear additive autoregressive model with exogenous input.

   M. Riedl, A. Suhrbier, H. Malberg, and 4 more authors

   Physical review. E, Statistical, nonlinear, and soft matter physics, Jul 2008

   Place: United States

   Abs Link

   The parameters of heart rate variability and blood pressure variability have proved to be useful analytical tools in cardiovascular physics and medicine. Model-based analysis of these variabilities additionally leads to new prognostic information about mechanisms behind regulations in the cardiovascular system. In this paper, we analyze the complex interaction between heart rate, systolic blood pressure, and respiration by nonparametric fitted nonlinear additive autoregressive models with external inputs. Therefore, we consider measurements of healthy persons and patients suffering from obstructive sleep apnea syndrome (OSAS), with and without hypertension. It is shown that the proposed nonlinear models are capable of describing short-term fluctuations in heart rate as well as systolic blood pressure significantly better than similar linear ones, which confirms the assumption of nonlinear controlled heart rate and blood pressure. Furthermore, the comparison of the nonlinear and linear approaches reveals that the heart rate and blood pressure variability in healthy subjects is caused by a higher level of noise as well as nonlinearity than in patients suffering from OSAS. The residue analysis points at a further source of heart rate and blood pressure variability in healthy subjects, in addition to heart rate, systolic blood pressure, and respiration. Comparison of the nonlinear models within and among the different groups of subjects suggests the ability to discriminate the cohorts that could lead to a stratification of hypertension risk in OSAS patients.

4. Circulatory soluble endoglin and its predictive value for preeclampsia in second-trimester pregnancies with abnormal uterine perfusion.

   Holger Stepan, Annegret Geipel, Friederike Schwarz, and 3 more authors

   American journal of obstetrics and gynecology, Feb 2008

   Place: United States

   Abs Link

   OBJECTIVE: Soluble endoglin (sEng) is increased dramatically in preeclampsia and acts synergistically with soluble fms-like tyrosine kinase 1 (sFlt1) to promote the preeclamptic phenotype. The aim of this study was to investigate whether the sEng increase was present already in second-trimester pregnancies with abnormal uterine perfusion and whether the pregnancy was at risk for preeclampsia. STUDY DESIGN: This prospective study includes 77 second-trimester pregnant women with abnormal uterine perfusion. sEng and sFlt1 were measured with an enzyme-linked immunosorbent assay. RESULTS: Adverse pregnancy outcome was associated with higher sEng levels in the second trimester. SEng was highest in those pregnancies with early-onset preeclampsia. Combined analysis of sEng and sFlt1 is able to predict early-onset preeclampsia with a sensitivity of 100% and a specificity of 93.3%. CONCLUSION: Elevated sEng levels are detectable in second-trimester pregnancies with abnormal uterine perfusion and subsequent pregnancy complications. The concurrent measurement of uterine perfusion and angiogenic factors allows a highly efficient prediction of early-onset preeclampsia.

2007

1. Introduction: Cardiovascular physics.

   Niels Wessel, Jürgen Kurths, William Ditto, and 1 more author

   Chaos (Woodbury, N.Y.), Mar 2007

   Place: United States

   Abs Link

   The number of patients suffering from cardiovascular diseases increases unproportionally high with the increase of the human population and aging, leading to very high expenses in the public health system. Therefore, the challenge of cardiovascular physics is to develop high-sophisticated methods which are able to, on the one hand, supplement and replace expensive medical devices and, on the other hand, improve the medical diagnostics with decreasing the patient’s risk. Cardiovascular physics-which interconnects medicine, physics, biology, engineering, and mathematics-is based on interdisciplinary collaboration of specialists from the above scientific fields and attempts to gain deeper insights into pathophysiology and treatment options. This paper summarizes advances in cardiovascular physics with emphasis on a workshop held in Bad Honnef, Germany, in May 2005. The meeting attracted an interdisciplinary audience and led to a number of papers covering the main research fields of cardiovascular physics, including data analysis, modeling, and medical application. The variety of problems addressed by this issue underlines the complexity of the cardiovascular system. It could be demonstrated in this Focus Issue, that data analyses and modeling methods from cardiovascular physics have the ability to lead to significant improvements in different medical fields. Consequently, this Focus Issue of Chaos is a status report that may invite all interested readers to join the community and find competent discussion and cooperation partners.

2. Cardiovascular and respiratory dynamics during normal and pathological sleep.

   Thomas Penzel, Niels Wessel, Maik Riedl, and 6 more authors

   Chaos (Woodbury, N.Y.), Mar 2007

   Place: United States

   Abs Link

   Sleep is an active and regulated process with restorative functions for physical and mental conditions. Based on recordings of brain waves and the analysis of characteristic patterns and waveforms it is possible to distinguish wakefulness and five sleep stages. Sleep and the sleep stages modulate autonomous nervous system functions such as body temperature, respiration, blood pressure, and heart rate. These functions consist of a sympathetic tone usually related to activation and to parasympathetic (or vagal) tone usually related to inhibition. Methods of statistical physics are used to analyze heart rate and respiration to detect changes of the autonomous nervous system during sleep. Detrended fluctuation analysis and synchronization analysis and their applications to heart rate and respiration during sleep in healthy subjects and patients with sleep disorders are presented. The observed changes can be used to distinguish sleep stages in healthy subjects as well as to differentiate normal and disturbed sleep on the basis of heart rate and respiration recordings without direct recording of brain waves. Of special interest are the cardiovascular consequences of disturbed sleep because they present a risk factor for cardiovascular disorders such as arterial hypertension, cardiac ischemia, sudden cardiac death, and stroke. New derived variables can help to find indicators for these health risks.

3. The angiotensin-(1-7) receptor agonist AVE0991 dominates the circadian rhythm and baroreflex in spontaneously hypertensive rats.

   N. Wessel, H. Malberg, S. Heringer-Walther, and 2 more authors

   Journal of cardiovascular pharmacology, Feb 2007

   Place: United States

   Abs Link

   Because we previously suggested the endogenous heptapeptide angiotensin (Ang)-(1-7) to be involved in the improvement of baroreflex sensitivity observed in spontaneously hypertensive rats (SHR), we here investigated the role of the heptapeptide in blood pressure control under physiologic conditions in awake SHR using the first nonpeptide, orally applicable Ang-(1-7) receptor agonist AVE0991 by telemetry. Five weeks after the start of treatment the blood pressure signals (500 Hz) were monitored in 10 untreated and 6 age-matched male SHR treated by AVE0991 for 24 hours (every 2 hours for 10 minutes). The autonomous tone was estimated from the heart rate and blood pressure variability (HRV, BPV) and from the spontaneous baroreceptor sensitivity (BRS).AVE0991 treatment blunted the rodent-characterizing nightly increase in blood pressure and led to pronounced changes in the BPV and HRV parameters during the night in comparison to untreated controls (eg, sdNN: AVE0991=8.19 versus control=11.5 mm Hg; P\textless0.001). However, even more significant differences were detected for BRS. Whereas the average slope did not alter, the activation of the baroreflexes (P\textless10E-6) and the number of baroreflex fluctuations were reduced dramatically by AVE0991 (P\textless10E-5). The data obtained pointed to an abating impact of AVE0991 on the baroreceptor in SHR and to its influence on the circadian rhythm, thus implying a direct involvement of Ang-(1-7) in cardiovascular control.

4. Cardiac magnetic field map topology quantified by Kullback-Leibler entropy identifies patients with hypertrophic cardiomyopathy.

   A. Schirdewan, A. Gapelyuk, R. Fischer, and 6 more authors

   Chaos (Woodbury, N.Y.), Mar 2007

   Place: United States

   Abs Link

   Hypertrophic cardiomyopathy (HCM) is a common primary inherited cardiac muscle disorder, defined clinically by the presence of unexplained left ventricular hypertrophy. The detection of affected patients remains challenging. Genetic testing is limited because only in 50%-60% of all HCM diagnoses an underlying mutation can be found. Furthermore, the disease has a varied clinical course and outcome, with many patients having little or no discernible cardiovascular symptoms, whereas others develop profound exercise limitation and recurrent arrhythmias or sudden cardiac death. Therefore prospective screening of HCM family members is strongly recommended. According to the current guidelines this includes serial echocardiographic and electrocardiographic examinations. In this study we investigated the capability of cardiac magnetic field mapping (CMFM) to detect patients suffering from HCM. We introduce for the first time a combined diagnostic approach based on map topology quantification using Kullback-Leibler (KL) entropy and regional magnetic field strength parameters. The cardiac magnetic field was recorded over the anterior chest wall using a multichannel-LT-SQUID system. CMFM was calculated based on a regular 36 point grid. We analyzed CMFM in patients with confirmed diagnosis of HCM (HCM, n=33, 43.8+/-13 years, 13 women, 20 men), a control group of healthy subjects (NORMAL, n=57, 39.6+/-8.9 years; 22 women and 35 men), and patients with confirmed cardiac hypertrophy due to arterial hypertension (HYP, n=42, 49.7+/-7.9 years, 15 women and 27 men). A subgroup analysis was performed between HCM patients suffering from the obstructive (HOCM, n=19) and nonobstructive (HNCM, n=14) form of the disease. KL entropy based map topology quantification alone identified HCM patients with a sensitivity of 78.8% and specificity of 86.9% (overall classification rate 84.8%). The combination of the KL parameters with a regional field strength parameter improved the overall classification rate to 87.9% (sensitivity: 84.8%, specificity: 88.9%, area under ROC curve: 0.94). KL measures applied to discriminate between HOCM and HNCM patients showed a correct classification of 78.8%. The combination of one KL and one regional parameter again improved the overall classification rate to 97%. A preliminary prospective analysis in two HCM families showed the feasibility of this diagnostic approach with a correct diagnosis of all 22 screened family members (1 HOCM, 4 HNCM, 17 normal). In conclusion, Cardiac Magnetic Field Mapping including KL entropy based topology quantifications is a suitable tool for HCM screening.

5. Asymmetry of the acceleration and deceleration capacity of heart rate is strongly dependent on ventricular premature complexes.

   Niels Wessel, Shishir Dash, Jürgen Kurths, and 2 more authors

   Biomedizinische Technik. Biomedical engineering, Jun 2007

   Place: Germany

   Abs Link

   In this letter, we explain the role of acceleration and deceleration capacities as novel risk predictors after myocardial infarction and their relation to the occurrence of ventricular premature complexes.

6. Detection of patients with coronary artery disease using cardiac magnetic field mapping at rest.

   Andrej Gapelyuk, Niels Wessel, Robert Fischer, and 8 more authors

   Journal of electrocardiology, Oct 2007

   Place: United States

   Abs Link

   We studied the use of cardiac magnetic field mapping to detect patients with CAD without subjecting them to stress. Fifty-nine healthy control subjects and 101 patients with CAD without previous MI were included. The optimal positions for detecting CAD were located in the left superior parasternal and in the inferior midsternal area. Values for ST slope, ST shift, T peak amplitude, ST-T integral, and magnetic field map orientation differed significantly between the 2 groups. Three parameters together in a multivariate analysis yielded a sensitivity of 84% and a specificity of 83% in distinguishing patients with CAD from control subjects. We suggest that cardiac magnetic field mapping is a promising technique to identify patients with CAD.

7. Autonomic control in patients experiencing atrial fibrillation after cardiac surgery.

   Robert Bauernschmitt, Hagen Malberg, Niels Wessel, and 6 more authors

   Pacing and clinical electrophysiology : PACE, Jan 2007

   Place: United States

   Abs Link

   BACKGROUND: Atrial fibrillation (AF) occurs in 20-40% of patients after open heart surgery and leads to an increased morbidity and prolonged hospital stay. Earlier studies have demonstrated that depressed baroreflex function predicts mortality and major arrhythmic events in patients surviving myocardial infarction. Cardiac surgery per se leads to decreased baroreflex sensitivity (BRS) and heart rate variability (HRV). Hence, the present study was aimed at analyzing the impact of the cardiovascular autonomous system on the development of postsurgical AF. METHODS AND RESULTS: The study covered 51 patients who consecutively underwent aortic valve replacement, coronary artery bypass surgery, or combined procedures. Noninvasive blood pressure and ECG were recorded the day before and 24 hour after surgery. BRS, linear as well as nonlinear HRV parameters were calculated using established methods. Eighteen patients developed AF during the first postoperative week, while 33 remained in sinus rhythm (SR) throughout the observation period. Patients with postoperative (PostOp) AF exhibited a significantly reduced preoperative (PreOp) BRS in terms of bradycardic and tachycardic regulation (average delayed slope [ms/mmHg]: SR: PreOp: 9.83 +/- 3.26, PostOp: 6.02 +/- 2.29, Pre-Post: P \textless 0.001; AF: PreOp: 7.59 +/- 1.99, PostOp: 6.39 +/- 3.67, Pre-Post: P \textless 0.044; AF vs SR: PreOp: P \textless 0.01, PostOp: ns). In both groups, surgery caused a decrease of BRS and HRV. Analysis of nonlinear dynamics revealed a tendency toward decreased system complexity caused by the operation; this trend was significant in patients remaining in sinus rhythm. CONCLUSIONS: Patients experiencing postoperative AF obviously suffer from an impaired BRS before surgery already. These findings may be used to guide prophylactic antiarrhythmic therapy.

8. Autonomic cardiac control in animal models of cardiovascular diseases II. Variability analysis in transgenic rats with alpha-tropomyosin mutations Asp175Asn and Glu180Gly.

   Dirk Wernicke, Niels Wessel, Hagen Malberg, and 3 more authors

   Biomedizinische Technik. Biomedical engineering, Feb 2007

   Place: Germany

   Abs Link

   Animal models of cardiovascular diseases allow to investigate relevant pathogenetic mechanisms in detail. In the present study, the mutations Asp175Asn and Glu180Gly in alpha-tropomyosin (TPM1), known cause familiar hypertrophic cardiomyopathy (FHC) were studied for changes in hemodynamic parameters and spontaneous baroreflex regulation in transgenic rats in comparison to transgenic and non-transgenic controls by telemetry. Heart rate variability (HRV) and blood pressure variability (BPV) were analyzed using time- and frequency domain, as well as non-linear measures. The dual sequence method was used for the estimation of the baroreflex regulation. In transgenic rats harboring mutated TPM1, changes in HRV were detected during exercise, but not at rest. Both mutations, Asp175Asn and Glu180Gly, caused increased low frequency power. In addition, in animals with mutation Asp175Asn a reduced total HRV was observed. BPV did not show any differences between all transgenic animal lines. During exercise, a strong increase in the number of bradycardic and tachycardic fluctuations accompanied with decreased baroreflex sensitivity (BRS) was detected in animals with either TPM1 mutation, Asp175Asn or Glu180Gly. These data suggest, that the analysis of cardiac autonomic control, particularly of baroreflex regulation, represents a powerful non-invasive approach to investigate the effects of subtle changes in sarcomeric architecture on cardiac physiology in vivo. In case of mutations Asp175Asn or Glu180Gly in TPM1, early detection of alterations in autonomic cardiac control could help to prevent sudden cardiac death in affected persons.

9. Autonomic cardiac control in animal models of cardiovascular diseases. I. Methods of variability analysis.

   Niels Wessel, Robert Bauernschmitt, Dirk Wernicke, and 2 more authors

   Biomedizinische Technik. Biomedical engineering, Feb 2007

   Place: Germany

   Abs Link

   Analysis of heart rate variability (HRV) and blood pressure variability (BPV) and baroreceptor sensitivity (BRS) has become a proven tool in clinical cardiovascular diagnostics and risk stratification. In the present work, traditional and new methodological approaches for analysis of HRV, BPV, and BRS data are summarized. HRV, BPV, and BRS parameters were obtained from animal studies designed to study pathogenetic mechanisms of distinct cardiovascular diseases. Different non-linear approaches for HRV and BPV analysis are presented here, in particular measures of complexity based on symbolic dynamics. The dual sequence method (DSM) was employed for BRS analysis. In comparison to the classical measure of BRS using the average slope [ms/mm Hg], DSM offers additional information about the time-variant coupling between BPV and HRV. Since cardiovascular regulation shares common features among different species, data on HRV and BPV, as well as BRS, in animal models might be useful for understanding the pathogenetic mechanisms of cardiovascular diseases in humans and in the development of new diagnostic approaches.

10. Analysis of cardiovascular oscillations: a new approach to the early prediction of pre-eclampsia.

    H. Malberg, R. Bauernschmitt, A. Voss, and 4 more authors

    Chaos (Woodbury, N.Y.), Mar 2007

    Place: United States

    Abs Link

    Pre-eclampsia (PE) is a serious disorder with high morbidity and mortality occurring during pregnancy; 3%-5% of all pregnant women are affected. Early prediction is still insufficient in clinical practice. Although most pre-eclamptic patients show pathological uterine perfusion in the second trimester, this parameter has a positive predictive accuracy of only 30%, which makes it unsuitable for early, reliable prediction. The study is based on the hypothesis that alterations in cardiovascular regulatory behavior can be used to predict PE. Ninety-six pregnant women in whom Doppler investigation detected perfusion disorders of the uterine arteries were included in the study. Twenty-four of these pregnant women developed PE after the 30th week of gestation. During pregnancy, additional several noninvasive continuous blood pressure recordings were made over 30 min under resting conditions by means of a finger cuff. The time series extracted of systolic as well as diastolic beat-to-beat pressures and the heart rate were studied by variability and coupling analysis to find predictive factors preceding genesis of the disease. In the period between the 18th and 26th weeks of pregnancy, three special variability and baroreflex parameters were able to predict PE several weeks before clinical manifestation. Discriminant function analysis of these parameters was able to predict PE with a sensitivity and specificity of 87.5% and a positive predictive value of 70%. The combined clinical assessment of uterine perfusion and cardiovascular variability demonstrates the best current prediction several weeks before clinical manifestation of PE.

11. Predictive value of maternal angiogenic factors in second trimester pregnancies with abnormal uterine perfusion.

    Holger Stepan, Angela Unversucht, Niels Wessel, and 1 more author

    Hypertension (Dallas, Tex. : 1979), Apr 2007

    Place: United States

    Abs Link

    Angiogenic factors like placental growth factor and its antiangiogenic antagonist soluble fms-like tyrosine kinase 1 (sFlt1) are closely related to the pathogenesis of preeclampsia and intrauterine growth restriction. Because it is known that altered maternal sFlt1 and placental growth factor levels are detectable weeks before the onset of these pregnancy complications, it was the aim of the study to investigate the predictive value of these markers in high-risk second trimester pregnancies characterized by abnormal uterine perfusion. This prospective study includes 63 second trimester pregnant women with abnormal uterine perfusion. Twenty five of them developed a later complication (12 with preeclampsia, 11 with intrauterine growth restriction, and 2 with intrauterine death), whereas 38 had a normal course of pregnancy. Pregnancies with adverse pregnancy outcome showed in the second trimester significantly higher sFlt1 (1403.6+/-555 versus 451.8+/-42 pg/mL; P\textless0.05) and lower placental growth factor (139.6+/-24 versus 184.1+/-21 pg/mL) levels compared with those with normal outcome. These alterations were more pronounced in pregnancies with subsequent preeclampsia compared with intrauterine growth restriction and early onset diseases (delivery \textless34 weeks) compared with late-onset diseases. The combination of Doppler and sFlt1 increases the sensitivity of Doppler alone for iatrogenic preterm delivery from 64% up to 79% and the specificity from 63% up to 80%. Using both factors, sFlt1 and placental growth factor, early onset preeclampsia can be predicted with 83% sensitivity and 95% specificity. We conclude that the concurrent measurement of uterine perfusion and angiogenic factors allows an efficient prediction of early onset pregnancy complications, particularly preeclampsia.

12. Scaling characteristics of heart rate time series before the onset of ventricular tachycardia.

    Mathias Baumert, Niels Wessel, Alexander Schirdewan, and 2 more authors

    Annals of biomedical engineering, Feb 2007

    Place: United States

    Abs Link

    Ventricular tachycardia (VT) provokes sudden cardiac death (SCD), which is a major cause of mortality in developed countries. Implantable cardioverter-defibrillators (ICDs) are an efficient therapy for SCD prevention. In this study we analyze heart rate variability (HRV) in data stored by ICDs. In 29 patients exhibiting VT episodes, the last 1000 normal beat-to-beat intervals are analyzed and compared to an individually acquired control time series (CON). HRV analysis is performed with standard parameters of time and frequency domain as suggested by the HRV Task Force. For scaling analyses of heart rate time series, the fractal dimension is analysed, applying Higuchi’s algorithm (HFD). Furthermore, detrended fluctuation analysis (DFA) is performed. None of the standard HRV parameters shows significant differences between CON and VT. Before the onset of VT, the scaling characteristics by means of HFD and DFA are significantly changed. In conclusion, scaling analysis reveals changes in autonomic heart rate modulation preceding VT.

2006

1. Toward a prediction of sudden death in propofol-related infusion syndrome.

   Niels Wessel, and Alexander Schirdewan

   Heart rhythm, Feb 2006

   Place: United States

   Link
2. Relation between circulating angiotensin II type 1 receptor agonistic autoantibodies and soluble fms-like tyrosine kinase 1 in the pathogenesis of preeclampsia.

   H. Stepan, R. Faber, N. Wessel, and 3 more authors

   The Journal of clinical endocrinology and metabolism, Jun 2006

   Place: United States

   Abs Link

   CONTEXT: Placental and circulatory soluble fms-like tyrosine kinase 1 (sFlt1) has proven to be elevated in pregnant women with preeclampsia, a disease characterized by hypertension, proteinuria, and endothelial dysfunction. Recent studies also demonstrated an autoantibody against the angiotensin II type 1 (AT1) receptor (AT1-AA) in that disease. OBJECTIVE: Both factors are discussed as key players in the etiology of preeclampsia. However, it has not yet been clarified whether these two circulating factors correlate and whether synergy determines the severity of pathology. DESIGN: AT1-AA was retrospectively determined by a bioassay and sFlt1 by an ELISA. PATIENTS: Serum from second-trimester pregnancies with normal or abnormal uterine perfusion and in women at term with or without pregnancy pathology was analyzed. RESULTS: Most of the preeclamptic patients were characterized by high sFlt1 levels and the presence of AT1-AA, although the agonistic effects of the antibody did not correlate with the sFlt1 concentrations (P = 0.85). Although AT1-AA was also detected in second-trimester pregnancies evidencing abnormal uterine perfusion without later pathology, sFlt1 was not significantly elevated in these pregnancies, compared with those with normal uterine perfusion. However, whereas women with abnormal perfusion and later pregnancy pathology did not differ in AT1-AA, compared with those with normal outcome, sFlt1 was significantly increased. Again, the two factors did not correlate (P = 0.15). CONCLUSIONS: We conclude that AT1-AA bioactivity and sFlt1 concentrations do not correlate, are not mutually dependent, and are thus probably involved in distinct pathogenetic mechanisms. Both factors in combination may not be causative for the early impaired trophoblast invasion and pathological uterine perfusion.

3. Does the C-type natriuretic peptide have prognostic value in chagas disease and other dilated cardiomyopathies?

   Silvia Heringer-Walther, Maria da Consolação V. Moreira, Niels Wessel, and 4 more authors

   Journal of cardiovascular pharmacology, Dec 2006

   Place: United States

   Abs Link

   Atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP) are powerful neurohormonal indicators of left-ventricular function and prognosis in heart failure (HF). Chagas disease (CD) caused by the protozoan Trypanosoma cruzi remains a major cause of HF in Latin America. We assessed whether the plasma concentration of the third natriuretic peptide, C-type natriuretic peptide (CNP), also has diagnostic and prognostic properties in patients with CD or other dilated cardiomyopathies (DCM). Blood samples were obtained from 66 patients with CD, 50 patients with DCM from other causes, and 30 gender- and age-matched healthy subjects. Patients were subdivided according to the New York Heart Association (NYHA) class. The CNP concentration was determined by radioimmunoassay (Immundiagnostik, Bensheim, Germany). The main duration of follow-up was 31.4 months (range 13 to 54 months); 19 patients had died and 11 patients received a heart transplant. CNP concentrations were only significantly altered in patients with DCM or CD of the NYHA classes III and IV (P \textless 0.05). The Pearson correlation of echocardiographic data with CNP revealed an association only with the left-ventricular end systolic volume (P = 0.03) in patients with DCM. Furthermore, CNP did not predict mortality or the necessity for heart transplant. Our data are the first to demonstrate the raised levels of the third natriuretic peptide CNP in CD and other DCM. Whereas ANP and BNP have a high predictive value for mortality in both diseases, CNP is without any predictive potency.

4. Normalized correlation dimension for heart rate variability analysis.

   Corinna Raab, Jürgen Kurths, Alexander Schirdewan, and 1 more author

   Biomedizinische Technik. Biomedical engineering, Oct 2006

   Place: Germany

   Abs Link

   In this paper we use the concept of large-scale dimension densities to analyze heart rate variability data. This method uses a normalized Grassberger-Procaccia algorithm and estimates the dimension in the rather large scales of the system. This enables us to analyze very short data. First we re-analyze data from the CIC 2002 challenge and can completely distinguish between real data and computer-generated data using only one parameter. We then analyze unfiltered data for 15 patients with atrial fibrillation (AF), 15 patients with congestive heart failure (CHF), 15 elderly healthy subjects, and 18 young healthy subjects. This method can completely separate the AF group from the other groups and the CHF patients show significant differences compared to the young and elderly healthy volunteers. Furthermore, differences are evident in the dimensionality between day and night for healthy persons, but not for the CHF patients. Finally, the results are compared to standard heart rate variability parameters.

5. Comparison of three methods for beat-to-beat-interval extraction from continuous blood pressure and electrocardiogram with respect to heart rate variability analysis.

   Alexander Suhrbier, Rafael Heringer, Thomas Walther, and 2 more authors

   Biomedizinische Technik. Biomedical engineering, Jul 2006

   Place: Germany

   Abs Link

   In recent years the analysis of heart rate variability (HRV) has become a suitable method for characterizing autonomous cardiovascular regulation. The aim of this study was to investigate the differences in HRV estimated from continuous blood pressure (BP) measurement by different methods in comparison to electrocardiogram (ECG) signals. The beat-to-beat intervals (BBI) were simultaneously extracted from the ECG and blood pressure of 9 cardiac patients (10 min, Colin system, 1000-Hz sampling frequency). For both data types, slope, peak, and correlation detection algorithms were applied. The short-term variability was calculated using concurrent 10-min BP and ECG segments. The root mean square errors in comparison to ECG slope detection were: 1.74 ms for ECG correlation detection; 5.42 ms for ECG peak detection; 5.45 ms for BP slope detection; 5.75 ms for BP correlation detection; and 11.96 ms for BP peak detection. Our results show that the variability obtained with ECG is the most reliable. Moreover, slope detection is superior to peak detection and slightly superior to correlation detection. In particular, for ECG signals with higher frequency characteristics, peak detection often exhibits more artificial variability. Besides measurement noise, respiratory modulation and pulse transit time play an important role in determining BBI. The slope detection method applied to ECG should be preferred, because it is more robust as regards morphological changes in the signals, as well as physiological properties. As the ECG is not recorded in most animal studies, distal pulse wave measurement in combination with correlation or slope detection may be considered an acceptable alternative.

6. Nonlinear additive autoregressive model-based analysis of short-term heart rate variability.

   Niels Wessel, Hagen Malberg, Robert Bauernschmitt, and 2 more authors

   Medical & biological engineering & computing, Apr 2006

   Place: United States

   Abs Link

   In this contribution we test the hypothesis that nonlinear additive autoregressive model-based data analysis improves the diagnostic ability based on short-term heart rate variability. For this purpose, a nonlinear regression approach, namely, the maximal correlation method is applied to the data of 37 patients with dilated cardiomyopathy as well as of 37 age- and sex-matched healthy subjects. We find that this approach is a powerful tool in discriminating both groups and promising for further model-based analyses.

7. A combined technique for predicting pre-eclampsia: concurrent measurement of uterine perfusion and analysis of heart rate and blood pressure variability.

   Thomas Walther, Niels Wessel, Hagen Malberg, and 3 more authors

   Journal of hypertension, Apr 2006

   Place: Netherlands

   Abs Link

   OBJECTIVE: Pre-eclampsia is a serious complication of pregnancy with high morbidity and mortality and an incidence of 3-5% in all pregnancies. Early prediction is still insufficient in clinical practice. Although most pre-eclamptic patients have pathological uterine perfusion in the second trimester, perfusion disturbance has a positive predictive accuracy (PPA) only of approximately 30%. METHODS: Non-invasive continuous blood pressure recordings were taken simultaneously via a finger cuff for 30 min. Time series of systolic as well as diastolic beat-to-beat pressure values were extracted to analyse heart rate and blood pressure variability and baroreflex sensitivity in 102 second-trimester pregnancies, to assess predictability for pre-eclampsia (n = 16). All women underwent Doppler investigations of the uterine arteries. RESULTS: We identified a combination of three variability and baroreflex parameters to best predict pre-eclampsia several weeks before clinical manifestation. The discriminant function of these three parameters classified patients with later pre-eclampsia with a sensitivity of 87.5%, a specificity of 83.7%, and a PPA of 50.0%. Combined with Doppler investigations of uterine arteries, PPA increased to 71.4%. CONCLUSIONS: This technique of incorporating one-stop clinical assessment of uterine perfusion and variability parameters in the second trimester produces the most effective prediction of pre-eclampsia to date.

8. Large-scale dimension densities for heart rate variability analysis.

   Corinna Raab, Niels Wessel, Alexander Schirdewan, and 1 more author

   Physical review. E, Statistical, nonlinear, and soft matter physics, Apr 2006

   Place: United States

   Abs Link

   In this work, we reanalyze the heart rate variability (HRV) data from the 2002 Computers in Cardiology (CiC) Challenge using the concept of large-scale dimension densities and additionally apply this technique to data of healthy persons and of patients with cardiac diseases. The large-scale dimension density (LASDID) is estimated from the time series using a normalized Grassberger-Procaccia algorithm, which leads to a suitable correction of systematic errors produced by boundary effects in the rather large scales of a system. This way, it is possible to analyze rather short, nonstationary, and unfiltered data, such as HRV. Moreover, this method allows us to analyze short parts of the data and to look for differences between day and night. The circadian changes in the dimension density enable us to distinguish almost completely between real data and computer-generated data from the CiC 2002 challenge using only one parameter. In the second part we analyzed the data of 15 patients with atrial fibrillation (AF), 15 patients with congestive heart failure (CHF), 15 elderly healthy subjects (EH), as well as 18 young and healthy persons (YH). With our method we are able to separate completely the AF (rho (mu/ls) = 0.97 +/- 0.02) group from the others and, especially during daytime, the CHF patients show significant differences from the young and elderly healthy volunteers (CHF, 0.65 +/- 0.13; EH, 0.54 +/- 0.05; YH, 0.57 +/- 0.05; p \textless 0.05 for both comparisons). Moreover, for the CHF patients we find no circadian changes in rho (mu/ls) (day, 0.65 +/- 0.13; night, 0.66 +/- 0.12; n.s.) in contrast to healthy controls (day, 0.54 +/- 0.05; night, 0.61 +/- 0.05; p=0.002). Correlation analysis showed no statistical significant relation between standard HRV and circadian LASDID, demonstrating a possibly independent application of our method for clinical risk stratification.

2005

1. Towards robotic heart surgery: introduction of autonomous procedures into an experimental surgical telemanipulator system.

   R. Bauernschmitt, E. U. Schirmbeck, A. Knoll, and 5 more authors

   The international journal of medical robotics + computer assisted surgery : MRCAS, Sep 2005

   Place: England

   Abs Link

   The introduction of telemanipulator systems into cardiac surgery enabled the heart surgeon to perform minimally invasive procedures with high precision and stereoscopic view. For further improvement and especially for inclusion of autonomous action sequences, implementation of force-feedback is necessary. The aim of our study was to provide a robotic scenario giving the surgeon an impression very similar to open procedures (high immersion) and to enable autonomous surgical knot tying with delicate suture material. In this experimental set-up the feasibility of autonomous surgical knot tying is demonstrated for the first time using stereoscopic view and force feedback.

2. Longitudinal analysis of heart rate variability in chronic hypertensive pregnancy.

   Thomas Walther, Niels Wessel, Mathias Baumert, and 3 more authors

   Hypertension research : official journal of the Japanese Society of Hypertension, Feb 2005

   Place: England

   Abs Link

   In the US, it is currently estimated that 3% of pregnant women have chronic hypertension, or more than 100,000 pregnant women each year. The aim of our study was to investigate the adaptation of autonomic control during pregnancy based on heart rate variability analysis and to determine whether chronic hypertension during pregnancy has an impact on this adaptation. Sixteen pregnant women with chronic hypertension (CH group; mean age, 30 years; range, 25-33 years) and 35 healthy pregnant women serving as controls (CON group; mean age, 28 years; range, 24-30 years) were recruited for this longitudinal study. Beginning at the 20th week of pregnancy, the women were monitored every 4th week until delivery. For the analysis of heart rate variability, Portapres signals (200 Hz) were recorded for 30 min under resting conditions. Women in the CH group had significantly elevated blood pressure compared to controls (CON, 111 mmHg [105-132]; CH, 140 mmHg [132-148]; p\textless0.001). An increased heart rate was found in both groups during the second half of pregnancy. Consequently, decreased heart rate variability was observed, but was more pronounced in the CON group. There was a shift in the frequency bands indicated by an elevation of the low-to-high frequency ratio (LF/HF) in both groups due to a decrease in HF, and thus a significant increase in LFn (LF power in normalized units). However, VLF (power of very low frequency range) increased exclusively in the CON pregnancies. Our data showed no significant difference in heart rate variability between the subjects of the CH and CON groups. Longitudinal variations were detectable in normal pregnancies and also, albeit to a lesser degree, in chronic hypertensive pregnant women. Thus, our data indicate that patients with long-term hypertension are still able to respond to the physiological changes occurring during pregnancy.

3. Brain natriuretic peptide predicts survival in Chagas’ disease more effectively than atrial natriuretic peptide.

   S. Heringer-Walther, M. C. V. Moreira, N. Wessel, and 7 more authors

   Heart (British Cardiac Society), Mar 2005

   Place: England

   Link
4. Correlation dimension analysis of heart rate variability in patients with dilated cardiomyopathy.

   Raúl Carvajal, Niels Wessel, Montserrat Vallverdú, and 2 more authors

   Computer methods and programs in biomedicine, May 2005

   Place: Ireland

   Abs Link

   A correlation dimension analysis of heart rate variability (HRV) was applied to a group of 55 patients with dilated cardiomyopathy (DCM) and 55 healthy subjects as controls. The 24-h RR time series for each subject was divided into segments of 10,000 beats to determine the correlation dimension (CD) per segment. A study of the influence of the time delay (lag) in the calculation of CD was performed. Good discrimination between both groups (p\textless0.005) was obtained with lag values of 5 or greater. CD values of DCM patients (8.4+/-1.9) were significantly lower than CD values for controls (9.5+/-1.9). An analysis of CD values of HRV showed that for healthy people, CD night values (10.6+/-1.8) were significant greater than CD day values (9.2+/-1.9), revealing a circadian rhythm. In DCM patients, this circadian rhythm was lost and there were no differences between CD values in day (8.8+/-2.4) and night (8.9+/-2.1).

2004

1. Impairment of cardiovascular autonomic control in patients early after cardiac surgery.

   R. Bauernschmitt, H. Malberg, N. Wessel, and 3 more authors

   European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, Mar 2004

   Place: Germany

   Abs Link

   OBJECTIVE: Impairment of the baroreceptor reflex activity reflects an alteration of the autonomous regulation of the cardiovascular system and has proven to predict fatal outcome in patients after acute myocardial infarction. The following study was performed to analyse the baroreceptor sensitivity, heart rate variability and blood pressure variability in patients early after coronary surgery. METHODS: Twenty-five male patients undergoing coronary artery bypass were examined in a prospective study; normal values were obtained from healthy volunteers. Arterial pressure signals were recorded from a radial artery catheter for 30 min preoperatively and in short intervals after surgery. Mechanical manipulations and pharmacological interventions were avoided during the sampling periods. Baroreflex function was calculated according to the dual sequence method, heart rate variability and blood pressure variability were calculated including nonlinear methods. RESULTS: Initial values of the patients did not differ from healthy volunteers. The strength of baroreflex sensitivity (increase in blood pressure causing a synchronous decrease of heart rate) is low 2 h postoperatively. The number of delayed tachycardic changes of heart rate, which are caused by sympathetic activation, is only moderately reduced as compared to values obtained from healthy volunteers. Heart rate variability is widely unchanged as compared to preoperative values; blood pressure variability showed an increase of low-frequency components, again indicating sympathetic predominance. Nonlinear analyses revealed reduced system complexity at the beginning of the postoperative course. CONCLUSION: Obviously, there is a vagal suppression 20 h after surgery, while the sympathetic tonus works in a normal range. This unbalanced interaction of the autonomous systems is similar to findings in patients after myocardial infarction. The predictive value of these markers has to be elucidated in further clinical studies.

2. alpha-Tropomyosin mutations Asp(175)Asn and Glu(180)Gly affect cardiac function in transgenic rats in different ways.

   Dirk Wernicke, Corinna Thiel, Corina M. Duja-Isac, and 14 more authors

   American journal of physiology. Regulatory, integrative and comparative physiology, Sep 2004

   Place: United States

   Abs Link

   To study the mechanisms by which missense mutations in alpha-tropomyosin cause familial hypertrophic cardiomyopathy, we generated transgenic rats overexpressing alpha-tropomyosin with one of two disease-causing mutations, Asp(175)Asn or Glu(180)Gly, and analyzed phenotypic changes at molecular, morphological, and physiological levels. The transgenic proteins were stably integrated into the sarcomere, as shown by immunohistochemistry using a human-specific anti-alpha-tropomyosin antibody, ARG1. In transgenic rats with either alpha-tropomyosin mutation, molecular markers of cardiac hypertrophy were induced. Ca(2+) sensitivity of cardiac skinned-fiber preparations from animals with mutation Asp(175)Asn, but not Glu(180)Gly, was decreased. Furthermore, elevated frequency and amplitude of spontaneous Ca(2+) waves were detected only in cardiomyocytes from animals with mutation Asp(175)Asn, suggesting an increase in intracellular Ca(2+) concentration compensating for the reduced Ca(2+) sensitivity of isometric force generation. Accordingly, in Langendorff-perfused heart preparations, myocardial contraction and relaxation were accelerated in animals with mutation Asp(175)Asn. The results allow us to propose a hypothesis of the pathogenetic changes caused by alpha-tropomyosin mutation Asp(175)Asn in familial hypertrophic cardiomyopathy on the basis of changes in Ca(2+) handling as a sensitive mechanism to compensate for alterations in sarcomeric structure.

3. Heart rate turbulence: higher predictive value than other risk stratifiers?

   Niels Wessel, Hagen Malberg, and Thomas Walther

   Circulation, Mar 2004

   Place: United States

   Link
4. Baroreflex sensitivity, heart rate, and blood pressure variability in hypertensive pregnancy disorders.

   R. Faber, M. Baumert, H. Stepan, and 3 more authors

   Journal of human hypertension, Oct 2004

   Place: England

   Abs Link

   Hypertensive pregnancy disorders are a leading cause of perinatal and maternal morbidity and mortality. Heart rate variability (HRV), blood pressure variability (BPV), and baroreflex sensitivity (BRS) are relevant predictors of cardiovascular risk in humans. The aim of the study was to evaluate whether HRV, BPV, and BRS differ between distinct hypertensive pregnancy disorders. Continuous heart rate and blood pressure recordings were performed in 80 healthy pregnant women as controls (CON), 19 with chronic hypertension (CH), 18 with pregnancy-induced hypertension (PIH), and 44 with pre-eclampsia (PE). The data were assessed by time and frequency domain analysis, nonlinear dynamics, and BRS. BPV is markedly altered in all three groups with hypertensive disorders compared to healthy pregnancies, whereby changes were most pronounced in PE patients. Interestingly, this increase in PE patients did not lead to elevated spontaneous baroreflex events, while BPV changes in both the other hypertensive groups were paralleled by alterations in baroreflex parameters. The HRV is unaltered in CH and PE but significantly impaired in PIH. We conclude that parameters of the HRV, BPV, and BRS differ between various hypertensive pregnancy disorders. Thus, distinct clinical manifestations of hypertension in pregnancy have different pathophysiological, regulatory, and compensatory mechanisms.

5. Short-term heart rate turbulence analysis versus variability and baroreceptor sensitivity in patients with dilated cardiomyopathy.

   Hagen Malberg, Robert Bauernschmitt, Udo Meyerfeldt, and 2 more authors

   Indian pacing and electrophysiology journal, Oct 2004

   Place: Netherlands

   Abs

   New methods for the analysis of arrhythmias and their hemodynamic consequences have been applied in risk stratification, in particular to patients after myocardial infarction. This study investigates the suitability of short-term heart rate turbulence (HRT) analysis in comparison to heart rate and blood pressure variability as well as baroreceptor sensitivity analyses to characterise the regulatory differences between patients with dilated cardiomyopathy (DCM) and healthy controls. In this study, 30 minutes data of non-invasive continuous blood pressure and ECGs of 37 DCM patients and 167 controls measured under standard resting conditions were analysed. The results show highly significant differences between DCM patients and controls in heart rate and blood pressure variability as well as in baroreceptor sensitivity parameters. Applying a combined heart rate-blood pressure trigger, ventricular premature beats were detected in 24.3% (9) of the DCM patients and 11.3% (19) of the controls. This fact demonstrates the limited applicability of short-term HRT analyses. However, the HRT parameters showed significant differences in this subgroup with ventricular premature beats (turbulence onset: DCM: 1.80+/-2.72, controls: - 4.34+/-3.10, p\textless0.001; turbulence slope: DCM: 6.75+/-5.50, controls: 21.30+/-17.72, p=0.021). Considering all (including HRT) parameters in the subgroup with ventricular beats, a discrimination rate between DCM patients and controls of 88.0% was obtained (max. 6 parameters). The corresponding value obtained for the total group was 86.3% (without HRT parameters). Comparable classification rates and high correlations between heart rate turbulence and variability and baroreflex parameters point to a more universal applicability of the latter methods.

6. Predicting thermal displacements in modular tool systems.

   Niels Wessel, Jan Konvicka, Frank Weidermann, and 5 more authors

   Chaos (Woodbury, N.Y.), Mar 2004

   Place: United States

   Abs Link

   In the last decade, there has been an increasing interest in compensating thermally induced errors to improve the manufacturing accuracy of modular tool systems. These modular tool systems are interfaces between spindle and workpiece and consist of several complicatedly formed parts. Their thermal behavior is dominated by nonlinearities, delay and hysteresis effects even in tools with simpler geometry and it is difficult to describe it theoretically. Due to the dominant nonlinear nature of this behavior the so far used linear regression between the temperatures and the displacements is insufficient. Therefore, in this study we test the hypothesis whether we can reliably predict such thermal displacements via nonlinear temperature-displacement regression functions. These functions are estimated first from learning measurements using the alternating conditional expectation (ACE) algorithm and then tested on independent data sets. First, we analyze data that were generated by a finite element spindle model. We find that our approach is a powerful tool to describe the relation between temperatures and displacements for simulated data. Next, we analyze the temperature-displacement relationship in a silent real experimental setup, where the tool system is thermally forced. Again, the ACE algorithm is powerful to estimate the deformation with high precision. The corresponding errors obtained by using the nonlinear regression approach are 10-fold lower in comparison to multiple linear regression analysis. Finally, we investigate the thermal behavior of a modular tool system in a working milling machine and again get promising results. The thermally induced errors can be estimated with 1-2 microm accuracy using this nonlinear regression analysis. Therefore, this approach seems to be very useful for the development of new modular tool systems.

7. Forecasting of life threatening arrhythmias using the compression entropy of heart rate.

   M. Baumert, V. Baier, J. Haueisen, and 4 more authors

   Methods of information in medicine, Mar 2004

   Place: Germany

   Abs

   OBJECTIVES: Ventricular tachycardia (VT) provoking sudden cardiac death (SCD) are a major cause of mortality in the developed countries. The most efficient therapy for SCD prevention are implantable cardioverter defibrillators (ICD). In this study heart rate variability (HRV) measures were analyzed for short-term forecasting of VT in order to improve VT sensing and to enable a patient warning of forth-coming shocks. METHODS: The last 1000 normal beat-to-beat intervals before 50 VT episodes stored by the ICD were analyzed and compared to individually acquired control time series (CON). HRV analysis was performed with standard parameters of time and frequency domain as suggested by the HRV Task Force and furthermore with a newly developed and optimized nonlinear parameter that assesses the compression entropy of heart rate (Hc). RESULTS: Except of meanNN (p = 0.02) we found no significant differences in standard HRV parameters. In contrast, Hc revealed highly significant (p = 0.007) alterations in VT compared with CON suggesting a decreased complexity before the onset of VT. CONCLUSION: Compression entropy might be a suitable parameter for short-term forecasting of life-threatening tachycardia in ICD.

2003

1. Intermittently decreased beat-to-beat variability in congestive heart failure.

   Niels Wessel, Alexander Schirdewan, and Jürgen Kurths

   Physical review letters, Sep 2003

   Place: United States

   Link
2. Brain natriuretic peptide as a predictor of cardiomyopathy in Chagas’ disease.

   Thomas Walther, Silvia Heringer-Walther, Niels Wessel, and 2 more authors

   Lancet (London, England), May 2003

   Place: England

   Link
3. [Short-term heart rate turbulence analysis versus variability and baroreceptor sensitivity in patients with dilated cardiomyopathy].

   H. Malberg, R. Bauernschmitt, U. Meyerfeldt, and 2 more authors

   Zeitschrift fur Kardiologie, Jul 2003

   Place: Germany

   Abs Link

   New methods for the analysis of arrhythmias and their hemodynamic consequences have been applied in risk stratification, particularly to patients after myocardial infarction. This study investigates the suitability of shortterm heart rate turbulence (HRT) in comparison to heart rate and blood pressure variability as well as baroreceptor sensitivity analyses to characterize the regulatory differences in patients with dilated cardiomyopathy (DCM) and healthy controls. In this study, 30 minutes data from noninvasive continuous blood pressure and ECG of 37 DCM patients and 167 controls under standard resting conditions were analyzed. The results showed highly significant differences between DCM patients and controls in heart rate and blood pressure variability as well as baroreceptor sensitivity parameters. Applying a combined heart rate-blood pressure trigger, in 24.3% (9) of the DCM patients and in 11.3% (19) of the controls ventricular premature beats were detected. This fact demonstrates the constricted applicability of short-term HRT analyses. However, the HRT parameters showed significant differences in this subgroup with ventricular premature beats (Turbulence Onset: DCM: 1.80+/-2.72, CONTROLS: -4.34+/-3.10, p\textless0.001; Turbulence Slope: DCM: 6.75+/-5.50, CONTROLS: 21.30+/-17.72, p = 0.021). Considering all (including HRT) parameters in the subgroup with ventricular beats, a discrimination rate between DCM patients and controls of 88.0% was obtained (max. 6 parameters). In comparison, in the total group this rate was 86.3% (without HRT parameters). The comparable classification rates and the high correlations between heart rate turbulence and variability and baroreflex parameters point to a more universal applicability of the last-mentioned methods.

4. Heart rate turbulance: an independant risk factor?

   Niels Wessel, and Hagen Malberg

   Journal of cardiovascular electrophysiology, Dec 2003

   Place: United States

   Link
5. Analytical model for a cooperative ballistic deposition in one dimension.

   M. Kamrul Hassan, Niels Wessel, and Jürgen Kurths

   Physical review. E, Statistical, nonlinear, and soft matter physics, Jun 2003

   Place: United States

   Abs Link

   We formulate a model for a cooperative ballistic deposition (CBD) process whereby the incoming particles are correlated with those already adsorbed via attractive force. The strength of the correlation is controlled by a tunable parameter a that interpolates the classical car parking problem at a=0, the ballistic deposition at a=1, and the CBD model at a\textgreater1. The effects of the correlation in the CBD model are as follows. The jamming coverage q(a) increases with the strength of attraction a due to an ever-increasing tendency of cluster formation. The system almost reaches the closest packing structure as a–\textgreaterinfinity but never forms a percolating cluster, which is typical of one-dimensional systems. In the large a regime, the mean cluster size k increases as a(1/2). Furthermore, the asymptotic approach towards the closest packing is purely algebraic both with a as q(infinity)-q(a) approximately a(-1/2) and with k as q(infinity)-q(k) approximately k(-1), where q(infinity) approximately 1.

2002

1. Recurrence-plot-based measures of complexity and their application to heart-rate-variability data.

   Norbert Marwan, Niels Wessel, Udo Meyerfeldt, and 2 more authors

   Physical review. E, Statistical, nonlinear, and soft matter physics, Aug 2002

   Place: United States

   Abs Link

   The knowledge of transitions between regular, laminar or chaotic behaviors is essential to understand the underlying mechanisms behind complex systems. While several linear approaches are often insufficient to describe such processes, there are several nonlinear methods that, however, require rather long time observations. To overcome these difficulties, we propose measures of complexity based on vertical structures in recurrence plots and apply them to the logistic map as well as to heart-rate-variability data. For the logistic map these measures enable us not only to detect transitions between chaotic and periodic states, but also to identify laminar states, i.e., chaos-chaos transitions. The traditional recurrence quantification analysis fails to detect the latter transitions. Applying our measures to the heart-rate-variability data, we are able to detect and quantify the laminar phases before a life-threatening cardiac arrhythmia occurs thereby facilitating a prediction of such an event. Our findings could be of importance for the therapy of malignant cardiac arrhythmias.

2. Heart rate variability before the onset of ventricular tachycardia: differences between slow and fast arrhythmias.

   Udo Meyerfeldt, Niels Wessel, Henry Schütt, and 7 more authors

   International journal of cardiology, Aug 2002

   Place: Netherlands

   Abs Link

   BACKGROUND: We tested whether or not heart rate variability (HRV) changes can serve as early signs of ventricular tachycardia (VT) and predict slow and fast VT in patients with an implantable cardioverter defibrillator (ICD). METHODS AND RESULTS: We studied the ICD stored 1000 beat-to-beat intervals before the onset of VT (131 episodes) and during a control time without VT (74 series) in 63 chronic heart failure ICD patients. Standard HRV parameters as well as two nonlinear parameters, namely ’Polvar10’ from symbolic dynamics and the finite time growth rates ’Fitgra9’ were calculated. Comparing the control and the VT series, no linear HRV parameter showed a significant difference. The nonlinear parameters detected a significant increase in short phases with low variability before the onset of VT (for time series with less than 10% ectopy, P\textless0.05). Subdividing VT into fast (cycle length \textlessor=270 ms) and slow (\textgreater270 ms) events, we found that the onset of slow VT was characterized by a significant increase in heart rate, whereas fast VT was triggered during decreased heart rates, compared to the control series. CONCLUSIONS: Our data may permit the development of automatic ICD algorithms based on nonlinear dynamic HRV parameters to predict VT before it starts. Furthermore, they may facilitate improved prevention strategies.

3. Potential of feature selection methods in heart rate variability analysis for the classification of different cardiovascular diseases.

   Agnes Schumann, Niels Wessel, Alexander Schirdewan, and 2 more authors

   Statistics in medicine, Aug 2002

   Place: England

   Abs Link

   In this study heart rate variability (HRV) analysis was applied to characterize patients suffering from coronary heart disease (CHD), dilated cardiomyopathy (DCM) and patients who had survived an acute myocardial infarction (MI). On the basis of several HRV parameters, an optimal discrimination between the different kinds of cardiovascular diseases and between the diseases and healthy controls (HC) was derived by feature selection and linear classification. For each task a small favourable subset of a set of 33 potentially interesting HRV measures was selected with the intention of improving the diagnostic value and facilitating the physiological interpretation of HRV analysis. Time- and frequency-domain parameters as well as parameters from non-linear dynamics were included in the analysis. With the expectation that different diseases are characterized by different phenomena, feature selection was applied for each task separately. Using the features optimal for one task to another task can reveal a loss in performance, but it turned out that one specific parameter set (set1: normalized low frequency LF/P and a non-linear variability measure WPSUM13) was applicable for all tasks, where diseased and healthy subjects have to be distinguished, without significant reduction in performance. This set seems to be a general marker for pathologic changes in HRV and might be used for early detection of heart diseases. The classification between different heart diseases requires another parameter set (set2: meanNN and sdaNN, reflecting the steady state behaviour of the heart rate and long and short term SEAR describing the spectral composition). However, the use of set1 for the separation of different kinds of diseases, where set2 is appropriate, led to significant reduction in performance and vice versa. This observation may be important for future developments of HRV measures especially suitable for the assessment of disease severity.

4. Advanced analysis of spontaneous baroreflex sensitivity, blood pressure and heart rate variability in patients with dilated cardiomyopathy.

   Hagen Malberg, Niels Wessel, Annett Hasart, and 2 more authors

   Clinical science (London, England : 1979), Apr 2002

   Place: England

   Abs

   Baroreflex sensitivity (BRS) is an important parameter in the classification of patients with reduced left ventricular function. This study aimed at investigating BRS in patients with dilated cardiomyopathy (DCM) and in healthy subjects (controls), as well as comparing the values of BRS parameters with parameters of heart rate variability (HRV) and blood pressure variability (BPV). ECG, continuous blood pressure and respiration curves were recorded for 30 min in 27 DCM patients and 27 control subjects. The Dual Sequence Method (DSM) includes the analysis of spontaneous fluctuations in systolic blood pressure and the corresponding beat-to-beat intervals of heart rate to estimate bradycardic, opposite tachycardic and delayed baroreflex fluctuations. The number of systolic blood pressure/beat-to-beat interval fluctuations in DCM patients was reduced in comparison with controls (DCM patients: male, 154.4+/-93.9 ms/mmHg; female, 93.7+/-40.5 ms/mmHg; controls: male, 245.5+/-112.9 ms/mmHg; female, 150.6+/-55.8 ms/mmHg, P\textless0.05). The average slope in DCM patients was lower than in controls (DCM, 5.3+/-1.9 ms/mmHg; controls, 8.0+/-5.4 ms/mmHg; P\textless0.05). Discriminant function analysis showed that, in the synchronous range of the standard sequence method, the DCM and control groups could be discriminated to only 76% accuracy, whereas the DSM gave an improved accuracy of 84%. The combination of six parameters of HRV, BPV and DSM gives an accuracy of classification of 96%, whereas six parameters of HRV and BPV could separate the two groups to only 88% accuracy. Thus the DSM leads to an improved characterization of autonomous regulation in order to differentiate between DCM patients and healthy subjects. BRS in DCM patients is significantly reduced and apparently less effective.

5. [Analysis of cardiovascular regulation after heart operation].

   H. Malberg, N. Wessel, B. Kopp, and 1 more author

   Biomedizinische Technik. Biomedical engineering, Apr 2002

   Place: Germany

   Abs Link

   Baroreflex sensitivity, heart rate and blood pressure variability have been proven to predict fatal outcome in patients after acute myocardial infarction. This study aims at investigating the time dependent alterations in cardiovascular control to find new predictive parameters for arrhythmic events after surgery. 25 male patients with coronary heart disease following an aortocoronary bypass surgery were examined. The results show significant alterations in sympathetic and vagal mediated regulation. The extubation after 6 hours seems to influence primarily the sympathetic activation. Obviously, there is a vagal suppression 20 h after surgery, while the sympathetic tonus works in a normal range. This unbalanced interaction of the autonomous system seems to be a reason for the high incidence of atrial tachycardias in the early period after cardiac surgery.

6. Model based analysis of the heart rate and blood pressure relationship.

   N. Wessel, H. Malberg, U. Meyerfeldt, and 2 more authors

   Biomedizinische Technik. Biomedical engineering, Apr 2002

   Place: Germany

   Abs Link

   The main intention of this contribution is to measure the coupling between bivariate time series using the dual sequence method to estimate the baroreflex as well as a nonlinear regression approach, namely the maximal correlation method, to get a better understanding of the underlying processes. The data we analyse are heart rate and blood pressure variability time series from 27 patients with dilated cardiomyopathy as well as from a control group of 27 age- and sex-matched healthy subjects. The results strongly indicate and confirm the mechanisms of respiratory sinus arrhythmia in heart rate. Revealing the coupling direction and the strength of coupling between heart rate and blood pressure via optimal transformations in addition to the baroreflex estimation seems to be a very promising approach.

2001

2000

1. Evaluation of renormalised entropy for risk stratification using heart rate variability data.

   N. Wessel, A. Voss, J. Kurths, and 3 more authors

   Medical & biological engineering & computing, Nov 2000

   Place: United States

   Abs Link

   Standard time and frequency parameters of heart rate variability (HRV) describe only linear and periodic behaviour, whereas more complex relationships cannot be recognised. A method that may be capable of assessing more complex properties is the non-linear measure of ’renormalised entropy.’ A new concept of the method, RE(AR), has been developed, based on a non-linear renormalisation of autoregressive spectral distributions. To test the hypothesis that renormalised entropy may improve the result of high-risk stratification after myocardial infarction, it is applied to a clinical pilot study (41 subjects) and to prospective data of the St George’s Hospital post-infarction database (572 patients). The study shows that the new RE(AR) method is more reproducible and more stable in time than a previously introduced method (p\textless0.001). Moreover, the results of the study confirm the hypothesis that on average, the survivors have negative values of RE(AR) (-0.11+/-0.18), whereas the non-survivors have positive values (0.03+/-0.22, p\textless0.01). Further, the study shows that the combination of an HRV triangular index and RE(AR) leads to a better prediction of sudden arrhythmic death than standard measurements of HRV. In summary, the new RE(AR) method is an independent measure in HRV analysis that may be suitable for risk stratification in patients after myocardial infarction.

2. Baroreflex sensitivity, heart rate, and blood pressure variability in normal pregnancy.

   A. Voss, H. Malberg, A. Schumann, and 4 more authors

   American journal of hypertension, Nov 2000

   Place: United States

   Abs Link

   Heart rate variability is a relevant predictor of cardiovascular risk in humans. However, to use heart and blood pressure (BP) variability or baroreflex sensitivity as markers for hypertensive pregnancy disorders, it is first necessary to describe these parameters in normal pregnancy. To accommodate the complexities of autonomic cardiovascular control we added parameter domains of nonlinear dynamics to conventional linear methods of time and frequency domains. The BP of 27 women with normal pregnancy and 14 nonpregnant women were monitored at a high resolution (200 Hz sampling frequency) using a Portapres for 30 min. The pregnant women were divided into groups of 32 or less or greater than 32 weeks of gestation. Pregnant and nonpregnant women were classified into subclasses of maternal age of less than 28 or 28 or more years. Except for two single parameter domains, we found no significant differences in heart rate and BP variability for pregnant women with different gestational age or different maternal age. Moreover, no significant differences in spontaneous baroreflex sensitivity could be found between pregnant women regardless of either their age or gestational age. In contrast, all measures of nonlinear dynamics of heart rate variability as well as all parameter domains of spontaneous baroreflex sensitivity showed significant changes between pregnant and nonpregnant women, whereas BP variability did not differ between those groups. This complex assessment of autonomic cardiovascular regulation has shown that the parameters tested are stable in the second half of normal pregnancy, and might have the potential to be excellent indicators of pathophysiologic conditions.

3. Short-term forecasting of life-threatening cardiac arrhythmias based on symbolic dynamics and finite-time growth rates.

   N. Wessel, C. Ziehmann, J. Kurths, and 3 more authors

   Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics, Jan 2000

   Place: United States

   Abs Link

   Ventricular tachycardia or fibrillation (VT-VF) as fatal cardiac arrhythmias are the main factors triggering sudden cardiac death. The objective of this study is to find early signs of sustained VT-VF in patients with an implanted cardioverter-defibrillator (ICD). These devices are able to safeguard patients by returning their hearts to a normal rhythm via strong defibrillatory shocks; additionally, they store the 1000 beat-to-beat intervals immediately before the onset of a life-threatening arrhythmia. We study these 1000 beat-to-beat intervals of 17 chronic heart failure ICD patients before the onset of a life-threatening arrhythmia and at a control time, i.e., without a VT-VF event. To characterize these rather short data sets, we calculate heart rate variability parameters from the time and frequency domain, from symbolic dynamics as well as the finite-time growth rates. We find that neither the time nor the frequency domain parameters show significant differences between the VT-VF and the control time series. However, two parameters from symbolic dynamics as well as the finite-time growth rates discriminate significantly both groups. These findings could be of importance in algorithms for next generation ICD’s to improve the diagnostics and therapy of VT-VF.

4. Altered heart rate and blood pressure variability in mice lacking the Mas protooncogene.

   T. Walther, N. Wessel, N. Kang, and 5 more authors

   Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, Jan 2000

   Place: Brazil

   Abs Link

   Heart rate variability is a relevant predictor of cardiovascular risk in humans. A significant genetic influence on heart rate variability is suggested, although the genes involved are ill-defined. The Mas-protooncogene encodes a G-protein-coupled receptor with seven transmembrane domains highly expressed in testis and brain. Since this receptor is supposed to interact with the signaling of angiotensin II, which is an important regulator of cardiovascular homeostasis, heart rate and blood pressure were analyzed in Mas-deficient mice. Using a femoral catheter the blood pressure of mice was measured for a period of 30 min and 250 data values per second were recorded. The mean values and range of heart rate and blood pressure were then calculated. Neither heart rate nor blood pressure were significantly different between knockout mice and controls. However, high resolution recording of these parameters and analysis of the data by non-linear dynamics revealed significant alterations in cardiovascular variability in Mas-deficient animals. In particular, females showed a strong reduction of heart rate variability. Furthermore, the data showed an increased sympathetic tone in knockout animals of both genders. The marked alterations detected in Mas-deficient mice of both genders suggest that the Mas-protooncogene is an important determinant of heart rate and blood pressure variability.

1995

1. Quantitative analysis of heart rate variability.

   J. Kurths, A. Voss, P. Saparin, and 3 more authors

   Chaos (Woodbury, N.Y.), Mar 1995

   Place: United States

   Abs Link

   In the modern industrialized countries every year several hundred thousands of people die due to sudden cardiac death. The individual risk for this sudden cardiac death cannot be defined precisely by common available, noninvasive diagnostic tools like Holter monitoring, highly amplified ECG and traditional linear analysis of heart rate variability (HRV). Therefore, we apply some rather unconventional methods of nonlinear dynamics to analyze the HRV. Especially, some complexity measures that are based on symbolic dynamics as well as a new measure, the renormalized entropy, detect some abnormalities in the HRV of several patients who have been classified in the low risk group by traditional methods. A combination of these complexity measures with the parameters in the frequency domain seems to be a promising way to get a more precise definition of the individual risk. These findings have to be validated by a representative number of patients. (c) 1995 American Institute of Physics.

2. Improved analysis of heart rate variability by methods of nonlinear dynamics.

   A. Voss, J. Kurths, H. J. Kleiner, and 2 more authors

   Journal of electrocardiology, Mar 1995

   Place: United States

   Abs Link

   The traditional analysis of heart rate variability (HRV) in the time and frequency domains seems to be an independent predictive marker for sudden cardiac death. Because the usual applied methods of HRV analysis describe only linear or strong periodic phenomena, the authors have developed new methods of HRV analysis based on nonlinear dynamics. In that way, parameters are extracted that quantify more complex processes and their complicated relationships. These methods are symbolic dynamics that describes the beat-to-beat dynamics and renormalized entropy that compares the complexity of power spectra on a normalized energy level. In an initial investigation, the HRV of 35 healthy subjects and 39 cardiac patients have been analyzed. Using discriminant functions, the authors found an optimal (100%) differentiation between the group of healthy subjects (even using only an age-matched subgroup of 12 subjects) and that of patients after myocardial infarction with a high electrical risk (Lown 4b). Applying this discriminant function to a group of patients with low electrical risk, four patients show the same behavior indicative of a high risk score, which might be a sign for a hidden high risk, two patients show healthy behavior, and the remaining patients show a separate pattern. The use of new methods of nonlinear dynamics in combination with parameters of the time and frequency domains in HRV offers possibilities for improved classification of HRV behavior. It is suggested that this could lead to a more detailed classification of individual high risk.