David Ojeda

Integration of detailed modules in a core model of body fluid homeostasis and blood pressure regulation

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.

Influence of Vagus Nerve Stimulation parameters on chronotropism and inotropism in heart failure

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.

Embedding a Cardiac Pulsatile Model Into an Integrated Model of the Cardiovascular Regulation for Heart Failure Followup

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.

Sensitivity Analysis and Parameter Estimation of a Coronary Circulation Model for Triple-Vessel Disease

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.

Model-Based Design and Experimental Validation of Control Modules for Neuromodulation Devices

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.

Model-based design of control modules for neuromodulation devices

Control systems design may be a difficult task when the system to be controlled is complex, poorly understood, and with limited observability. This is often the case of biological or physiological systems. In this paper, we present a model-based control design framework, which is adapted to the design of medical devices. This framework couples a control module, based on a classical PID controller, a model of the medical device, and a physiological model representing the cardiovascular responses to vagus nerve stimulation (VNS). An example is proposed in which the goal of the controller is to regulate instantaneous heart rate in real-time, by modulating the current delivered to the vagus nerve by the neuromodulator in an adaptive manner. Results of the definition of the control system with different controller parameters and for different model configurations are provided, showing the feasibility and usefulness of a model-based design in this context.

Sensitivity Analysis of Vagus Nerve Stimulation Parameters on Acute Cardiac Autonomic Responses: Chronotropic, Inotropic and Dromotropic Effects

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.

Analysis of a baroreflex model for the study of the chronotropic response to vagal nerve stimulation

This paper describes the integration of computational models of the cardiovascular system, the cardiac electrical activity and the baroreceptor reflex of the autonomic nervous system, with a model representing vagal nerve stimulation (VNS). Sensitivity analyses are performed in order to find the model parameters that produce significant effects on heart rate (chronotropic effect). The most significant parameters are adjusted in order to reproduce real data acquired from sheep suffering from heart failure, during VNS periods. Results show the potential of the model to generate realistic chronotropic responses to VNS.

A model-based approach for the evaluation of vagal and sympathetic activities in a newborn lamb

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.

Towards an atrio-ventricular delay optimization assessed by a computer model for cardiac resynchronization therapy

In this paper, lumped-parameter models of the cardiovascular system, the cardiac electrical conduction system and a pacemaker are coupled to generate mitral ow pro les for di erent atrio-ventricular delay (AVD) con gurations, in the context of cardiac resynchronization therapy (CRT). First, we perform a local sensitivity analysis of left ventricular and left atrial parameters on mitral ow characteristics, namely E and A wave amplitude, mitral ow duration, and mitral ow time integral. Additionally, a global sensitivity analysis over all model parameters is presented to screen for the most relevant parameters that a ect the same mitral ow characteristics. Results provide insight on the in uence of left ventricle and atrium in uence on mitral ow pro les. This information will be useful for future parameter estimation of the model that could reproduce the mitral ow pro les and cardiovascular hemodynamics of patients undergoing AVD optimization during CRT.