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We hypothesized that a multiparametric evaluation, based on the combination of electrocardiographic and echocardiographic parameters, could enhance the appraisal of the likelihood of reverse remodeling and prognosis of favorable clinical evolution to improve the response of cardiac resynchronization therapy (CRT). Three hundred and twenty-three heart failure patients were retrospectively included in this multicenter study. 221 patients (68%) were responders, defined by a decrease in left ventricle end-systolic volume ≥15% at the 6-month follow-up. In addition, strain data coming from echocardiography were analyzed with custom-made signal processing methods. Integrals of regional longitudinal strain signals from the beginning of the cardiac cycle to strain peak and to the instant of aortic valve closure were analyzed. QRS duration, septal flash and different other features manually extracted were also included in the analysis. The random forest (RF) method was applied to analyze the relative feature importance, to select the most significant features and to build an ensemble classifier with the objective of predicting response to CRT. The set of most significant features was composed of Septal Flash, E, E/A, E/EA, QRS, left ventricular end-diastolic volume and eight features extracted from strain curves. A Monte Carlo cross-validation method with 100 runs was applied, using, in each run, different random sets of 80% of patients for training and 20% for testing. Results show a mean area under the curve (AUC) of 0.809 with a standard deviation of 0.05. A multiparametric approach using a combination of echo-based parameters of left ventricular dyssynchrony and QRS duration helped to improve the prediction of the response to cardiac resynchronization therapy.

Aims: Early diagnosis of heart failure with preserved ejection fraction (HFpEF) by determination of diastolic dysfunction is challenging. Strain-volume loop (SVL) is a new tool to analyse left ventricular function. We propose a new semi-automated method to calculate SVL area and explore the added value of this index for diastolic function assessment., Method and Results: Fifty patients (25 amyloidosis, 25 HFpEF) were included in the study and compared with 25 healthy control subjects. Left ventricular ejection fraction was preserved and similar between groups. Classical indices of diastolic function were pathological in HFpEF and amyloidosis groups with greater left atrial volume index, greater mitral average E/e' ratio, faster tricuspid regurgitation (P < 0.0001 compared with controls). SVL analysis demonstrated a significant difference of the global area between groups, with the smaller area in amyloidosis group, the greater in controls and a mid-range value in HFpEF group (37 vs. 120 vs. 72 mL.%, respectively, P < 0.0001). Applying a linear discriminant analysis (LDA) classifier, results show a mean area under the curve of 0.91 for the comparison between HFpEF and amyloidosis groups., Conclusion: SVLs area is efficient to identify patients with a diastolic dysfunction. This new semi-automated tool is very promising for future development of automated diagnosis with machine-learning algorithms., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Suicide is the leading cause of non-natural death worldwide, and major depressive disorder (MDD) is the mood disorder with the highest prevalence among individuals with suicidal behaviour (SB). The role of inflammation and immunomodulation in mood disorders has raised interest in recent years, as inflammation biomarkers have been reported to be increased in mood disorder patients, suggesting a role of inflammation in their pathogenesis. The influence of inflammation on the haematopoietic production is well known; however, a comprehensive study of the haematopoietic production in patients with major depressive episodes (MDE) is lacking. We examined global haematopoietic parameters from complete blood counts (CBC) of patients with MDE, in search of prognostic patterns. MDE patients presented differences in several CBC parameters, differences that were clearly pronounced and/or significant in concurrence with suicide attempts (SA). Red and white blood cell lineage parameters were affected, suggesting general haematopoietic modulation or imbalance. We observed distinct haematological parameter changes in women versus men, with men presenting milder alterations than women. Interestingly, we found that the List of Threatening Experiences (LTE) score, but not the Childhood Trauma Questionnaire (CTQ), was associated with the haematopoietic alterations observed exclusively in women and, more importantly, served as a parameter to stratify female MDE patients based on concurrence or non-concurrence with SA. In conclusion, grades of haematopoietic modulation in MDE patients are associated with absence or presence of SA. Haematopoietic manifestations differ between men and women and, in the latter, are markedly influenced by late, and not early, traumatic events., Competing Interests: Conflict of interest All authors declare no conflict of interest relative to this study., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

This paper proposes a model-based estimation of left ventricular (LV) pressure for the evaluation of constructive and wasted myocardial work of patients with aortic stenosis (AS). A model of the cardiovascular system is proposed, including descriptions of i) cardiac electrical activity, ii) elastance-based cardiac cavities, iii) systemic and pulmonary circulations and iv) heart valves. After a sensitivity analysis of model parameters, an identification strategy was implemented using a Monte-Carlo cross-validation approach. Parameter identification procedure consists in two steps for the estimation of LV pressures: step 1) from invasive, intraventricular measurements and step 2) from non-invasive data. The proposed approach was validated on data obtained from 12 patients with AS. The total relative errors between estimated and measured pressures were on average 11.9% and 12.27% and mean R2 were equal to 0.96 and 0.91, respectively for steps 1 and 2 of parameter identification strategy. Using LV pressures obtained from non-invasive measurements (step 2) and patient-specific simulations, Global Constructive (GCW), Wasted (GWW) myocardial Work and Global Work Efficiency (GWE) parameters were calculated. Correlations between measures and model-based estimations were 0.88, 0.80, 0.91 respectively for GCW, GWW and GWE. The main contributions concern the proposal of the parameter identification procedure, applied on an integrated cardiovascular model, able to reproduce LV pressure specifically to each AS patient, by non-invasive procedures, as well as a new method for the non-invasive estimation of constructive, wasted myocardial work and work efficiency in AS., Competing Interests: The authors have declared that no competing interests exist.

The objective of the current study was to propose a sensitivity analysis of a 3D left ventricle model in order to assess the influence of parameters on myocardial mechanical dispersion. A finite element model of LV electro-mechanical activity was proposed and a screening method was used to evaluate the sensitivity of model parameters on the standard deviation of time to peak strain. Results highlight the importance of propagation parameters associated with septal and lateral segments activation. Simulated curves were compared to myocardial strains, obtained from echocardiography of one healthy subject and one patient diagnosed with intraventricular dyssynchrony and coronary artery disease. Results show a close match between simulation and clinical strains and illustrate the model ability to reproduce myocardial strains in the context of intraventricular dyssynchrony.

The present study aimed to further unravel the effects of nasal continuous positive airway pressure (nCPAP) on the cardiovascular and respiratory systems in the neonatal period. Six-hour polysomnographic recordings were first performed in seven healthy newborn lambs, aged 2-3 days, without and with nCPAP application at 6 cmH 2 O (nCPAP-6), in randomized order. The effects of nCPAP-6 on heart rate variability, respiratory rate variability, and cardiorespiratory interrelations were analyzed using a semiautomatic signal processing approach applied to ECG and respiration recordings. Thereafter, a cardiorespiratory mathematical model was adapted to the experimental conditions to gain further physiological interpretation and to simulate higher nCPAP levels (8 and 10 cmH 2 O). Results from the signal processing approach suggest that nCPAP-6 applied in newborns with healthy lungs: 1 ) increases heart rate and decreases the time and frequency domain indices of heart rate variability, especially those representing parasympathetic activity, while increasing the complexity of the RR-interval time series; 2 ) prolongs the respiratory cycle and expiration duration and decreases respiratory rate variability; and 3 ) slightly impairs cardiorespiratory interrelations. Model-based analysis revealed that nCPAP-6 increases the heart rate and decreases respiratory sinus arrhythmia amplitude, in association with a reduced parasympathetic efferent activity. These results were accentuated when simulating an increased CPAP level. Overall, our results provide a further understanding of the effects of nCPAP in neonates, in the absence of lung disease. NEW & NOTEWORTHY Application of nasal continuous positive airway pressure (CPAP) at 6 cmH 2 O, a level very frequently used in newborns, alters heart and respiratory rate variability, as well as cardiorespiratory interrelations in a full-term newborn model without lung disease. Moreover, whereas nasal CPAP at 6 cmH 2 O decreases parasympathetic efferent activity, there is no change in sympathetic efferent activity.

This paper proposes the integration and analysis of a closed-loop model of the baroreflex and cardiovascular systems, focused on a time-varying estimation of the autonomic modulation of heart rate in Brugada syndrome (BS), during exercise and subsequent recovery. Patient-specific models of 44 BS patients at different levels of risk (symptomatic and asymptomatic) were identified through a recursive evolutionary algorithm. After parameter identification, a close match between experimental and simulated signals (mean error = 0.81%) was observed. The model-based estimation of vagal and sympathetic contributions were consistent with physiological knowledge, enabling to observe the expected autonomic changes induced by exercise testing. In particular, symptomatic patients presented a significantly higher parasympathetic activity during exercise, and an autonomic imbalance was observed in these patients at peak effort and during post-exercise recovery. A higher vagal modulation during exercise, as well as an increasing parasympathetic activity at peak effort and a decreasing vagal contribution during post-exercise recovery could be related with symptoms and, thus, with a worse prognosis in BS. This work proposes the first evaluation of the sympathetic and parasympathetic responses to exercise testing in patients suffering from BS, through the recursive identification of computational models; highlighting important trends of clinical relevance that provide new insights into the underlying autonomic mechanisms regulating the cardiovascular system in BS. The joint analysis of the extracted autonomic parameters and classic electrophysiological markers could improve BS risk stratification., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Recent studies have shown that myocardial constructive work (CW) assessed by pressure-strain loops (PSLs) is an independent predictor of a volumetric response to cardiac resynchronization therapy (CRT). The aim of this study was to evaluate the role of CW in predicting the cardiac outcome of heart failure patients undergoing CRT., Methods: This is a retrospective study including 166 CRT candidates (ejection fraction [EF] ≤35%, QRS duration ≥120 milliseconds). Two-dimensional standard echocardiography and speckle-tracking echocardiography were performed before CRT and at 6-month follow-up. PSLs were used to assess myocardial CW., Results: After a median follow-up of 4 years (range 1.3-5 years), cardiac death occurred in 14 patients (8%). A multivariable Cox regression analysis including age, coronary artery disease, and septal flash showed that CW≤888 mm Hg% was the only independent predictor of cardiac mortality (hazard ratio 4.23, 95% CI 1.08-16.5, P = .03). After 6 months of CRT, a 15% reduction in left ventricular end-systolic volume was observed in 118 (71%) patients, and a CRT volumetric response was identified. Among CRT responders, the concomitant presence of CW ≤888 mm Hg% identified a subgroup of patients at high risk of cardiac death (P = .04 in the log-rank test). The addition of CW ≤888 mm Hg% to a model including age, coronary artery disease, septal flash, and CRT response caused a significant increase in model power for the prediction of cardiac death (χ 2 : 12.6 vs 25.7, P = .02)., Conclusions: The estimation of left ventricular CW by PSLs is a relatively novel tool that allows for the prediction of cardiac outcome in CRT candidates., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Hyperbilirubinemia (HB) is responsible for neonatal jaundice in 60% of term newborns and 90% of preterm infants. Neonatal HB can induce neurological damage (acute HB encephalopathy) and has been associated with persistent apneas. The objective of the present study was to investigate the immediate and delayed effects of moderate, clinically-relevant HB on cardiorespiratory control in preterm lambs. Two groups of five preterm lambs, namely control and HB, were studied. At day five of life, moderate HB (150-250 μmol/L) was induced and maintained during 17 h in the HB group while control lambs received a placebo solution. Six hours after HB onset, 7-h polysomnographic recordings with electrocardiogram (ECG) and respiratory (RESP) signals were performed to assess the immediate effects of HB on heart rate variability (HRV), respiratory rate variability (RRV), and cardiorespiratory interrelations. Identical recordings were repeated 72 h after HB induction to examine the delayed effects of HB on HRV, RRV and cardiorespiratory interrelations. Our results demonstrate a higher HRV and vagal activity immediately after induction of moderate HB. Meanwhile, a decrease in respiratory rate with an increase in both long- and short-term RRV was also noted, as well as a higher amplitude of the respiratory sinus arrhythmia and cardiorespiratory coupling. Seventy-two hours later, the alterations in HRV, RRV, and cardiorespiratory interrelations were attenuated, although a number of them were still present, suggesting a lasting influence of HB on the basal control of the cardiorespiratory system. Our results pave the way for studies in human preterms to assess the relevance of monitoring HRV, RRV, and cardiorespiratory interrelations to detect the acute neurological effects of HB and consequently adapt the treatment of neonatal jaundice.

Background: The estimation of myocardial work by pressure strain loops (PSLs) is a totally new non-invasive approach to assess myocardial performance, and its role in patients with hypertrophic cardiomyopathy is unknown. The aims of the present study are therefore: (a) to compare myocardial work in patients with non-obstructive hypertrophic cardiomyopathy (HCM) and in a subset of age-matched healthy controls and (b) to assess the correlation between myocardial work and left ventricular (LV) fibrosis., Design: Eighty-two patients with non-obstructive HCM (58 ± 14 years) and 20 age-matched healthy subjects (58 ± 7 years, P = 0.99) underwent standard and speckle-tracking echocardiography to assess myocardial dimensions and deformation parameters. PSLs analysis was used to estimate global myocardial constructive work (GCW) and wasted work (GWW). LV fibrosis was estimated at cardiac magnetic resonance (CMR) by qualitative assessment of late gadolinium enhancement (LGE), and significant fibrosis was defined as LGE in ≥2 LV segments., Results: Global constructive work (1599 ± 423 vs 2248 ± 249 mm Hg%, P < 0.0001) was significantly reduced in HCM compared to the control group. No difference was observed in GWW (141 ± 125 vs 101 ± 88 mm Hg%, P = 0.18) and LV ejection fraction (LVEF) (63 ± 13 vs 66 ± 4% P = 0.17) between the two groups. In HCM, GCW was the only predictor of LV fibrosis at multivariable analysis (OR 1.01, 95% CI: 0.99-1.08, P = 0.04). A cutoff value of 1623 mm Hg% (AUC 0.80, 95% CI: 0.66-0.93, P < 0.0001) was able to predict myocardial fibrosis with a good sensitivity and fair specificity (82% and 67%, respectively)., Conclusions: Global constructive work is significantly reduced in HCM despite normal LVEF and is associated with the LV fibrosis as assessed by LGE., (© 2018 Wiley Periodicals, Inc.)

Purpose: The area of left ventricular (LV) pressure-strain loop (PSL) is used as an index of regional myocardial work. The purpose of the present work is to compare the main segmental PSL markers and the derived global work indices, when they are calculated using an estimated pressure signal or an observed pressure signal., Methods and Results: In nine patients implanted with a bi-ventricular pace-maker (CRT), LV pressure was invasively measured in five conditions: CRT-off, LV-pacing, right ventricular-pacing and two different CRT-pacing. For each condition, systolic blood pressure was measured by brachial artery cuff-pressure and transthoracic echocardiography loops were recorded simultaneously. The error and relative root mean square error (rRMSE) between measured and estimated pressure were calculated for each patient and each configuration. Correlation coefficient (R2) and Bland-Altman (BA) analysis were performed for PSL area and work indices. A total of 43 different haemodynamic conditions were compared (774 segmental PSL). The global rRMSE between estimated and measured LV-pressure was 12.3 mmHg. The estimated and measured segmental LV-PSL were strongly correlated, with an R2 of 0.98. BA analysis shows that the mean bias for the estimation of segmental LV-PSL area is 86.0 mmHg.%. A significant bias effect with linearly increasing error with pressure values is observed. R2 ≥ 0.88 and a mean bias in BA analysis ≤41.4 mmHg.% was observed for the estimation of global myocardial work indices., Conclusion: The non-invasive estimation for LV pressure-strain loop area and the global myocardial work indices obtained from LV-PSL strongly correlates with invasive measurements.

A semi-automated processing approach was developed to assess the effects of early postnatal environmental tobacco smoke (ETS) on the cardiorespiratory control of newborn lambs. The system consists of several steps beginning with artifact rejection, followed by the selection of stationary segments, and ending with feature extraction. This approach was used in six lambs exposed to 20 cigarettes/day for the first 15 days of life, while another six control lambs were exposed to room air. On postnatal day 16, electrocardiograph and respiratory signals were obtained from a 6-h polysomnographic recording. The effects of postnatal ETS exposure on heart rate variability, respiratory rate variability, and cardiorespiratory interrelations were explored. The unique results suggest that early postnatal ETS exposure increases respiratory rate variability and decreases the coupling between cardiac and respiratory systems. Potentially harmful consequences in early life include unstable breathing and decreased adaptability of cardiorespiratory function, particularly during early life challenges, such as prematurity or viral infection. Graphical abstract ᅟ.

Objective: Vagus nerve stimulation (VNS) is a potential therapeutic approach in a number of clinical applications. Although VNS is commonly delivered in an open-loop approach, it is now recognized that closed-loop stimulation may be necessary to optimize the therapy. In this paper, we propose an original generic closed-loop control system that can be readily integrated into an implantable device and allows for the adaptive modulation of multiple VNS parameters., Methods: The proposed control method consists of a state transition model (STM), in which each state represents a set of VNS parameters, and a state transition algorithm that optimally selects the best STM state, minimizing the error between an observed physiological variable and a given target value. The proposed method has been integrated into a real-time adaptive VNS prototype system and has been applied here to the regulation of the instantaneous heart rate, working synchronously with cardiac cycles. A quantitative performance evaluation is performed on seven sheep by computing classical control performance indicators. A comparison with a proportional-integral (PI) controller is also performed., Results: The STM controller presents a median mean square error, overshoot, and settling time, respectively, equal to 622.21 ms , 72.8%, and 7.5 beats., Conclusion: The proposed control method yields satisfactory accuracy and time response, while presenting a number of benefits over classical PI controllers. It represents a feasible approach for multiparametric VNS control on implantable devices., Significance: Closed-loop multiparametric stimulation may improve response and minimize side effects on current pathologies treated by VNS.

The vagus nerve (VN) is involved in the autonomic regulation of many physiological systems (cardiovascular, respiratory, gastrointestinal, etc.) and its stimulation is already an approved therapy for refractory epilepsy and depression. Other pathologies are thought to be treatable through vagus nerve stimulation (VNS), such as heart failure, cardiac arrhythmia, inflammation or auto-immune diseases. However, the efficacy of the stimulation is not always optimal, partly due to the materials and the architecture of currently available electrodes. Standard electrodes, composed of metallic rings that stimulate the whole diameter of the nerve, are not adapted to experimentations involving spatial selectivity. Efficient and selective charge injection is usually difficult to achieve simultaneously, especially in experimental setups using rodents, due to the thin diameter of their VN. In this paper, we show that we can take advantage of the high charge injection property of conducting polymers to acutely stimulate the vagus nerve in rodents, using individual active electrodes with dimensions $725\,\,\mu \mathrm{m}\times \,450\,\,\mu\mathrm{m}$. A particular PEDOT:PSS architecture integrating 12 active electrodes is developed and applied to the VN of one rat. A closed-loop VNS system developed in our previous works is used to stimulate the VN while analyzing the heart rate response. Results show the feasibility of this kind of electrodes for acute VNS on rodents and open the path towards new experimentations focused on selective stimulation and recording.

Ventricular arrhythmias in Brugada syndrome (BS) typically occur at rest and especially during sleep, suggesting that changes in the autonomic modulation may play an important role in arrhythmogenesis. The autonomic response to exercise and subsequent recovery was evaluated on 105 patients diagnosed with BS (twenty-four were symptomatic), by means of a time-frequency heart rate variability (HRV) analysis, so as to propose a novel predictive model capable of distinguishing symptomatic and asymptomatic BS populations. During incremental exercise, symptomatic patients showed higher HFnu values, probably related to an increased parasympathetic modulation, with respect to asymptomatic subjects. In addition, those extracted HRV features best distinguishing between populations were selected using a two-step feature selection approach, so as to build a linear discriminant analysis (LDA) classifier. The final features subset included one third of the total amount of extracted autonomic markers, mostly acquired during incremental exercise and active recovery, thus evidencing the relevance of these test segments in BS patients classification. The derived predictive model showed an improved performance with respect to previous works in the field (AUC = 0.92 ± 0.01; Se = 0.91 ± 0.06; Sp = 0.90 ± 0.05). Therefore, based on these findings, some of the analyzed HRV markers and the proposed model could be useful for risk stratification in Brugada syndrome.

Vagus nerve stimulation (VNS) is an established adjunctive therapy for pharmacologically refractory epilepsy and depression and is currently in active clinical research for other applications. In current clinical studies, VNS is delivered in an open-loop approach, where VNS parameters are defined during a manual titration phase. However, the physiological response to a given VNS configuration shows significant inter and intra-patient variability and may significantly evolve through time. VNS closed-loop approaches, allowing for the optimization of the therapy in an adaptive manner, may be necessary to improve efficacy while reducing side effects. This paper proposes a generic, closed-loop control VNS system that is able to optimize a number of VNS parameters in an adaptive fashion, in order to keep a control variable within a specified range. Although the proposed control method is completely generic, an example application using the cardiac beat to beat interval (RR) as control variable will be developed in this paper. The proposed controller is based on a state transition model (STM) that can be configured using a partially or a fully-connected architecture, different model orders and different state-transition algorithms. The controller is applied to the adaptive regulation of heart rate and evaluated on 6 sheep, for 13 different targets, using partially-connected STM with 10 states. Also, partially and fully-connected STM defined by 30 states were applied to 7 other sheep for the same 10 targets. Results illustrate the interest of the proposed fully-connected STM and the feasibility of integrating this control system into an implantable neuromodulator.

A method for the recursive identification of physiological models of the cardiovascular baroreflex is proposed and applied to the time-varying analysis of vagal and sympathetic activities. The proposed method was evaluated with data from five newborn lambs, which were acquired during injection of vasodilator and vasoconstrictors and the results show a close match between experimental and simulated signals. The model-based estimation of vagal and sympathetic contributions were consistent with physiological knowledge and the obtained estimators of vagal and sympathetic activities were compared to traditional markers associated with baroreflex sensitivity. High correlations were observed between traditional markers and model-based indices.

Although the therapeutic effects of Vagus Nerve Stimulation (VNS) have been recognized in pre-clinical and pilot clinical studies, the effect of different stimulation configurations on the cardiovascular response is still an open question, especially in the case of VNS delivered synchronously with cardiac activity. In this paper, we propose a formal mathematical methodology to analyze the acute cardiac response to different VNS configurations, jointly considering the chronotropic, dromotropic and inotropic cardiac effects. A latin hypercube sampling method was chosen to design a uniform experimental plan, composed of 75 different VNS configurations, with different values for the main parameters (current amplitude, number of delivered pulses, pulse width, interpulse period and the delay between the detected cardiac event and VNS onset). These VNS configurations were applied to 6 healthy, anesthetized sheep, while acquiring the associated cardiovascular response. Unobserved VNS configurations were estimated using a Gaussian process regression (GPR) model. In order to quantitatively analyze the effect of each parameter and their combinations on the cardiac response, the Sobol sensitivity method was applied to the obtained GPR model and inter-individual sensitivity markers were estimated using a bootstrap approach. Results highlight the dominant effect of pulse current, pulse width and number of pulses, which explain respectively 49.4%, 19.7% and 6.0% of the mean global cardiovascular variability provoked by VNS. More interestingly, results also quantify the effect of the interactions between VNS parameters. In particular, the interactions between current and pulse width provoke higher cardiac effects than the changes on the number of pulses alone (between 6 and 25% of the variability). Although the sensitivity of individual VNS parameters seems similar for chronotropic, dromotropic and inotropic responses, the interacting effects of VNS parameters provoke significantly different cardiac responses, showing the feasibility of a parameter-based functional selectivity. These results are of primary importance for the optimal, subject-specific definition of VNS parameters for a given therapy and may lead to new closed-loop methods allowing for the optimal adaptation of VNS therapy through time., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CH and JLB are employees of SORIN CRM SAS. PM is consultant for SORIN CRM SAS. No other conflicts are reported. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: Neural signals along the vagus nerve (VN) drive many somatic and autonomic functions. The clinical interest of VN stimulation (VNS) is thus potentially huge and has already been demonstrated in epilepsy. However, side effects are often elicited, in addition to the targeted neuromodulation., Approach: This review examines the state of the art of VNS applied to two emerging modulations of autonomic function: heart failure and obesity, especially morbid obesity., Main Results: We report that VNS may benefit from improved stimulation delivery using very advanced technologies. However, most of the results from fundamental animal studies still need to be demonstrated in humans.

This paper describes the integration of mathematical models of the cardiac electrical activity, the cardiovascular system and the baroreceptor reflex control of the autonomic nervous system, with a model representing a head-up tilt test. Sensitivity analyses are performed in order to determine those model parameters producing the greatest significant effects on heart rate and blood pressure. An optimization step is then applied to the most influential parameters in order to find the best model fit to real cardiac data obtained from a patient suffering from Brugada syndrome and a healthy subject, in supine and upright postures during a tilt test. Results show the feasibility of the model to generate realistic autonomic responses to head-up tilt testing in health and disease.

Goal: The goal of this paper is to propose a model-based control design framework, adapted to the development of control modules for medical devices. A particular example is presented in which instantaneous heart rate is regulated in real-time, by modulating, in an adaptive manner, the current delivered to the vagus nerve by a neuromodulator., Methods: The proposed framework couples a control module, based on a classical PI controller, a mathematical model of the medical device, and a physiological model representing the cardiovascular responses to vagus nerve stimulation (VNS). In order to analyze and evaluate the behavior of the device, different control parameters are tested on a "virtual population," generated with the model, according to the Latin Hypercube sampling method. In particular, sensitivity analyses are applied for the identification of a domain of interest in the space of the control parameters. The obtained control parameter domain has been validated in an experimental evaluation on six sheep., Results: A range of control parameters leading to accurate results was successfully estimated by the proposed model-based design method. Experimental evaluation of the control parameters inside such a domain led to the best compromise between accuracy and time response of the VNS control., Conclusion: The feasibility and usefulness of the proposed model-based design method were shown, leading to a functional, real-time closed-loop control of the VNS for the regulation of heart rate.

The evaluation of the time-varying vagal and sympathetic contributions to heart rate remains a challenging task because the observability of the baroreflex is generally limited and the time-varying properties are difficult to take into account, especially in non-stationnary conditions. The objective is to propose a model-based approach to estimate the autonomic modulation during a pharmacological challenge. A recursive parameter identification method is proposed and applied to a mathematical model of the baroreflex, in order to estimate the time-varying vagal and sympathetic contributions to heart rate modulation during autonomic maneuvers. The model-based method was evaluated with data from five newborn lambs, which were acquired during injection of vasodilator and vasoconstrictor drugs, on normal conditions and under beta-blockers, so as to quantify the effect of the pharmacological sympathetic blockade on the estimated parameters. After parameter identification, results show a close match between experimental and simulated signals for the five lambs, as the mean relative root mean squared error is equal to 0.0026 (± 0.003). The error, between simulated and experimental signals, is significantly reduced compared to a batch identification of parameters. The model-based estimation of vagal and sympathetic contributions were consistent with physiological knowledge and, as expected, it was possible to observe an alteration of the sympathetic response under beta-blockers. The simulated vagal modulation illustrates a response similar to traditional heart rate variability markers during the pharmacological maneuver. The model-based method, proposed in the paper, highlights the advantages of using a recursive identification method for the estimation of vagal and sympathetic modulation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Mathematical models of the coronary circulation have been shown to provide useful information for the analysis of intracoronary blood flow and pressure measurements acquired during coronary artery bypass graft (CABG) surgery. Although some efforts towards the patient-specific estimation of model parameters have been presented in this context, they are based on simplifying hypotheses about the collateral circulation and do not take advantage of the whole set of data acquired during CABG. In order to overcome these limitations, this paper presents an exhaustive parameter sensitivity analysis and a multiobjective patient-specific parameter estimation method, applied to a model of the coronary circulation of patients with triple vessel disease. The results of the sensitivity analysis highlighted the importance of capillary and collateral development. On the other hand, the estimation method was applied to intraoperative clinical data from ten patients obtained during CABG, which permitted to assess patient-specific collateral vessel situations. These approaches provide new insights regarding the heterogeneous configuration of the collateral circulation.

Vagus nerve stimulation (VNS) is a potential therapeutic approach in a number of clinical applications. Although VNS is commonly delivered in an open-loop approach, it is now recognized that closed-loop approaches may be necessary to optimize the therapy and minimize side effects of neuro-stimulation devices. In this paper, we describe a prototype system for real-time control of the instantaneous heart rate, working synchronously with the heart period. As a first step, an on-off control method has been integrated. The system is evaluated on one sheep with induced heart failure, showing the interest of the proposed approach.

Vagus Nerve Stimulation (VNS) has been shown to be useful in heart failure patients, including antiarrhythmic effects, improvement of cardiac function and reduction of the mortality. However, the optimal configuration of VNS can be a difficult task, since there are several adjustable parameters, such as current amplitude (mA), pulse width (ms), burst frequency (Hz), number of pulses and, in the case of cardiac-triggered VNS, the delay (ms) between the R-wave and the beginning of the stimulation. The objective of this paper is to analyse the effect of these parameters, and their interaction, on the chronotropic and inotropic responses to vagal stimulation. 306 VNS sequences were tested on 12 sheep with induced heart failure. Autonomic markers of the chronotropic (changes in RR interval) and inotropic (changes in dP/dtmax) effects were extracted from the observed data. In order to analyse the influence of stimulation parameters on these markers, a sensitivity analysis method was applied. Results illustrate the strong interaction between the delay and the others parameters. The number of pulses, the current and the frequency seem to be particularly influent on chronotropism and inotropism although the effect of the frequency is highly non-linear or it depends on other parameters.

In this paper, a mathematical model of the respiratory mechanics is used to reproduce experimental signal waveforms acquired from three newborn lambs. As the main challenge is to determine specific lamb parameters, a sensitivity analysis has been realized to find the most influent parameters, which are identified using an evolutionary algorithm. Results show a close match between experimental and simulated pressure and flow waveforms obtained during spontaneous ventilation and pleural pressure variations acquired during the application of positive pressure, since root mean square errors equal to 0.0119, 0.0052 and 0.0094. The identified parameters were discussed in light of previous knowledge of respiratory mechanics in the newborn.

This paper proposes a baroreflex model and a recursive identification method to estimate the time-varying vagal and sympathetic contributions to heart rate variability during autonomic maneuvers. The baroreflex model includes baroreceptors, cardiovascular control center, parasympathetic and sympathetic pathways. The gains of the global afferent sympathetic and vagal pathways are identified recursively. The method has been validated on data from newborn lambs, which have been acquired during the application of an autonomic maneuver, without medication and under beta-blockers. Results show a close match between experimental and simulated signals under both conditions. The vagal and sympathetic contributions have been simulated and, as expected, it is possible to observe different baroreflex responses under beta-blockers compared to baseline conditions.

Computational models can help understand the hemodynamics of the coronary circulation, which is of the upmost importance to help clinicians before, during and after a coronary artery bypass graft surgery. In this paper, we propose a multiobjective optimization method for parameter estimation of a computational model representing the coronary circulation on patients with a triple vessel disease. This estimation was not based on any assumption regarding the development of the collateral circulation, like in previous works. Indeed, the collateral development of a given patient is estimated through the model parameters. Parameter estimation was performed using clinical data from three patients, obtained before and during an off-pump coronary artery bypass graft surgery (CABG). Results showed a better performance when comparing the simulation with clinical data, since the total error estimation for three patients was reduced by 40 ± 22%. Moreover, the proposed method provides new insight regarding the heterogeneous configuration of the alternative collateral vessels.

This paper presents a contribution to the definition of the interfaces required to perform heterogeneous model integration in the context of integrative physiology. A formalization of the model integration problem is proposed and a coupling method is presented. The extension of the classic Guyton model, a multi-organ, integrated systems model of blood pressure regulation, is used as an example of the application of the proposed method. To this end, the Guyton model has been restructured, extensive sensitivity analyses have been performed, and appropriate transformations have been applied to replace a subset of its constituting modules by integrating a pulsatile heart and an updated representation of the renin-angiotensin system. Simulation results of the extended integrated model are presented and the impacts of their integration within the original model are evaluated., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The analysis of followup data from patients suffering from heart failure is a difficult task, due to the complex and multifactorial nature of this pathology. In this paper, we present a coupled model, integrating a pulsatile heart into a model of the short to long-term regulations of the cardiovascular system. An interface method is proposed to couple these models, which present significantly different time scales. Results from a sensitivity analysis of the original and integrated models are proposed with simulations reproducing the main effects of the short- and long-term responses of an acute decompensated heart failure episode on a patient undergoing cardiac resynchronization therapy.

The role of modelling and simulation in the systemic analysis of living systems is now clearly established. Emerging disciplines, such as systems biology, and worldwide research actions, such as the Physiome Project or the Virtual Physiological Human, are based on an intensive use of modelling and simulation methodologies and tools. One of the key aspects in this context is to perform an efficient integration of various models representing different biological or physiological functions, at different resolutions, spanning through different scales. This paper presents a multiformalism modelling and simulation environment (M2SL) that has been conceived to ease model integration. A given model is represented as a set of coupled and atomic model components that may be based on different mathematical formalisms with heterogeneous structural and dynamical properties. A co-simulation approach is used to solve these hybrid systems. The pioneering model of the overall regulation of the cardiovascular system proposed by Guyton and co-workers in 1972 has been implemented under M2SL and a pulsatile ventricular model based on a time-varying elastance has been integrated in a multi-resolution approach. Simulations reproducing physiological conditions and using different coupling methods show the benefits of the proposed environment.

The ventricular pressure profile is characteristic of the cardiac contraction progress and is useful to evaluate the cardiac performance. In this contribution, a tissue-level electromechanical model of the left ventricle is proposed, to assist the interpretation of left ventricular pressure waveforms. The left ventricle has been modeled as an ellipsoid composed of twelve mechano-hydraulic sub-systems. The asynchronous contraction of these twelve myocardial segments has been represented in order to reproduce a realistic pressure profiles. To take into account the different energy domains involved, the tissue-level scale and to facilitate the building of a modular model, multiple formalisms have been used: Bond Graph formalism for the mechano-hydraulic aspects and cellular automata for the electrical activation. An experimental protocol has been defined to acquire ventricular pressure signals from three pigs, with different afterload conditions. Evolutionary Algorithms have been used to identify the model parameters in order to minimize the error between experimental and simulated ventricular pressure signals. Simulation results show that the model is able to reproduce experimental ventricular pressure. In addition, electro-mechanical activation times have been determined in the identification process. For example, the maximum electrical activation time is reached, respectively, 96.5, 139.3 and 131.5 ms for the first, second, and third pigs. These preliminary results are encouraging for the application of the model on non-invasive data like ECG, arterial pressure or myocardial strain.

Objective: Tissue Doppler imaging (TDI) is commonly used to evaluate regional ventricular contraction properties through the analysis of myocardial strain. During the clinical examination, a set of strain signals is acquired concurrently at different locations. However, the joint interpretation of these signals remains difficult. This paper proposes a model-based approach in order to assist the clinician in making an analysis of myocardial strain., Methods and Materials: The proposed method couples a model of the left ventricle, which takes into account cardiac electrical, mechanical and hydraulic activities with an adapted identification algorithm, in order to obtain patient-specific model representations. The proposed model presents a tissue-level resolution, adapted to TDI strain analysis. The method is applied in order to reproduce TDI strain signals acquired from two healthy subjects and a patient presenting with dilated cardiomyopathy (DCM)., Results: The comparison between simulated and experimental strains for the three subjects reflects a satisfying adaptation of the model on different strain morphologies. The mean error between real and synthesized signals is equal to 2.34% and 2.09%, for the two healthy subjects and 1.30% for the patient suffering from DCM. Identified parameters show significant electrical conduction and mechanical activation delays for the pathologic case and have shown to be useful for the localization of the failing myocardial segments, which are situated on the anterior and lateral walls of the ventricular base., Conclusion: The present study shows the feasibility of a model-based method for the analysis of TDI strain signals. The identification of delayed segments in the pathologic case produces encouraging results and may represent a way to better utilize the information included in strain signals and to improve the therapy assistance.

We present the current state of the development of the SAPHIR project (a Systems Approach for PHysiological Integration of Renal, cardiac and respiratory function). The aim is to provide an open-source multi-resolution modelling environment that will permit, at a practical level, a plug-and-play construction of integrated systems models using lumped-parameter components at the organ/tissue level while also allowing focus on cellular- or molecular-level detailed sub-models embedded in the larger core model. Thus, an in silico exploration of gene-to-organ-to-organism scenarios will be possible, while keeping computation time manageable. As a first prototype implementation in this environment, we describe a core model of human physiology targeting the short- and long-term regulation of blood pressure, body fluids and homeostasis of the major solutes. In tandem with the development of the core models, the project involves database implementation and ontology development.

This paper presents a model-based method for the analysis of respiratory signals specifically adapted to newborns. The model includes a description of upper airways, distensible and lower airways, lungs, chest wall, alveoli, pleura and respiratory muscle activity. The model was used in stationary and non-stationary conditions to simulate respiratory signals obtained in one newborn lamb in various physiological conditions. An identification algorithm was used to adapt the model parameters to lamb data. Finally, the identified parameters were compared to values previously reported in adult humans.

This paper presents a model-based method for the analysis of regional myocardial strain, based on echocardiography and Tissue Doppler Imaging (TDI). A multi-formalism, tissue-level electromechanical model of the left ventricle is proposed. The parameters of the model are identified in order to reproduce regional strain signal morphologies obtained from a healthy subject and a patient presenting a dilated cardiomyopathy. The parameters identified for the DCM patient allow the localization of the failing myocardial segments and may be useful for a better design of cardiac resynchronization therapy on heart failure patients.

We present progress on a comprehensive, modular, interactive modeling environment centered on overall regulation of blood pressure and body fluid homeostasis. We call the project SAPHIR, for "a Systems Approach for PHysiological Integration of Renal, cardiac, and respiratory functions". The project uses state-of-the-art multi-scale simulation methods. The basic core model will give succinct input-output (reduced-dimension) descriptions of all relevant organ systems and regulatory processes, and it will be modular, multi-resolution, and extensible, in the sense that detailed submodules of any process(es) can be "plugged-in" to the basic model in order to explore, eg. system-level implications of local perturbations. The goal is to keep the basic core model compact enough to insure fast execution time (in view of eventual use in the clinic) and yet to allow elaborate detailed modules of target tissues or organs in order to focus on the problem area while maintaining the system-level regulatory compensations.

In 1999, the Broward County Health Department and local community faith-based organizations collaborated to develop Churches United to Stop HIV (CUSH). CUSH has provided HIV prevention services to over 32,000 people, trained over 2,850 faith leaders, conducted over 1,000 risk assessments and provided HIV counseling and testing for over 825 people and technical assistance for 48 churches, including the development of a training manual. We report the development of this innovative program that demonstrates how collaborations between public health and faith-based organizations can connect science with communities.