Computational modeling of ventricular-ventricular interactions suggest a role in clinical conditions involving heart failure.

Introduction: The left (LV) and right (RV) ventricles are linked biologically, hemodynamically, and mechanically, a phenomenon known as ventricular interdependence. While LV function has long been known to impact RV function, the reverse is increasingly being realized to have clinical importance. Investigating ventricular interdependence clinically is challenging given the invasive measurements required, including biventricular catheterization, and confounding factors such as comorbidities, volume status, and other aspects of subject variability. Methods: Computational modeling allows investigation of mechanical and hemodynamic interactions in the absence of these confounding factors. Here, we use a threesegment biventricular heart model and simple circulatory system to investigate ventricular interdependence under conditions of systolic and diastolic dysfunction of the LV and RV in the presence of compensatory volume loading. We use the end-diastolic pressure-volume relationship, end-systolic pressure-volume relationship, Frank Starling curves, and cardiac power output as metrics. Results: The results demonstrate that LV systolic and diastolic dysfunction lead to RV compensation as indicated by increases in RV power. Additionally, RV systolic and diastolic dysfunction lead to impaired LV filling, interpretable as LV stiffening especially with volume loading to maintain systemic pressure. Discussion: These results suggest that a subset of patients with intact LV systolic function and diagnosed to have impaired LV diastolic function, categorized as heart failure with preserved ejection fraction (HFpEF), may in fact have primary RV failure. Application of this computational approach to clinical data sets, especially for HFpEF, may lead to improved diagnosis and treatment strategies and consequently improved outcomes.

Portal Venous Remodeling Determines the Pattern of Cirrhosis Decompensation: A Systems Analysis.

INTRODUCTION: As liver disease progresses, scarring results in worsening hemodynamics ultimately culminating in portal hypertension. This process has classically been quantified through the portosystemic pressure gradient (PSG), which is clinically estimated by hepatic venous pressure gradient (HVPG); however, PSG alone does not predict a given patient's clinical trajectory regarding the Baveno stage of cirrhosis. We hypothesize that a patient's PSG sensitivity to venous remodeling could explain disparate disease trajectories. METHODS: We created a computational model of the portal system in the context of worsening liver disease informed by physiologic measurements from the field of portal hypertension. We simulated progression of clinical complications, HVPG, and transjugular intrahepatic portosystemic shunt placement while only varying a patient's likelihood of portal venous remodeling. RESULTS: Our results unify hemodynamics, venous remodeling, and the clinical progression of liver disease into a mathematically consistent model of portal hypertension. We find that by varying how sensitive patients are to create venous collaterals with rising PSG we can explain variation in patterns of decompensation for patients with liver disease. Specifically, we find that patients who have higher proportions of portosystemic shunting earlier in disease have an attenuated rise in HVPG, delayed onset of ascites, and less hemodynamic shifting after transjugular intrahepatic portosystemic shunt placement. DISCUSSION: This article builds a computational model of portal hypertension which supports that patient-level differences in venous remodeling may explain disparate clinical trajectories of disease.

Systems analysis of the mechanisms governing the cardiovascular response to changes in posture and in peripheral demand during exercise.

Blood flows and pressures throughout the human cardiovascular system are regulated in response to various dynamic perturbations, such as changes to peripheral demands in exercise, rapid changes in posture, or loss of blood from hemorrhage, via the coordinated action of the heart, the vasculature, and autonomic reflexes. To assess how the systemic and pulmonary arterial and venous circulation, the heart, and the baroreflex work together to effect the whole-body responses to these perturbations, we integrated an anatomically-based large-vessel arterial tree model with the TriSeg heart model, models capturing nonlinear characteristics of the large and small veins, and baroreflex-mediated regulation of vascular tone and cardiac chronotropy and inotropy. The model was identified by matching data from the Valsalva maneuver (VM), exercise, and head-up tilt (HUT). Thirty-one parameters were optimized using a custom parameter-fitting tool chain, resulting in an unique, high-fidelity whole-body human cardiovascular systems model. Because the model captures the effects of exercise and posture changes, it can be used to simulate numerous clinical assessments, such as HUT, the VM, and cardiopulmonary exercise stress testing. The model can also be applied as a framework for representing and simulating individual patients and pathologies. Moreover, it can serve as a framework for integrating multi-scale organ-level models, such as for the heart or the kidneys, into a whole-body model. Here, the model is used to analyze the relative importance of chronotropic, inotropic, and peripheral vascular contributions to the whole-body cardiovascular response to exercise. It is predicted that in normal physiological conditions chronotropy and inotropy make roughly equal contributions to increasing cardiac output and cardiac power output during exercise. Under upright exercise conditions, the nonlinear pressure-volume relationship of the large veins and sympathetic-mediated venous vasoconstriction are both required to maintain preload to achieve physiological exercise levels. The developed modeling framework is built using the open Modelica modeling language and is freely distributed.

Hypoxic pulmonary vasoconstriction as a regulator of alveolar-capillary oxygen flux: A computational model of ventilation-perfusion matching.

The relationship between regional variabilities in airflow (ventilation) and blood flow (perfusion) is a critical determinant of gas exchange efficiency in the lungs. Hypoxic pulmonary vasoconstriction is understood to be the primary active regulator of ventilation-perfusion matching, where upstream arterioles constrict to direct blood flow away from areas that have low oxygen supply. However, it is not understood how the integrated action of hypoxic pulmonary vasoconstriction affects oxygen transport at the system level. In this study we develop, and make functional predictions with a multi-scale multi-physics model of ventilation-perfusion matching governed by the mechanism of hypoxic pulmonary vasoconstriction. Our model consists of (a) morphometrically realistic 2D pulmonary vascular networks to the level of large arterioles and venules; (b) a tileable lumped-parameter model of vascular fluid and wall mechanics that accounts for the influence of alveolar pressure; (c) oxygen transport accounting for oxygen bound to hemoglobin and dissolved in plasma; and (d) a novel empirical model of hypoxic pulmonary vasoconstriction. Our model simulations predict that under the artificial test condition of a uniform ventilation distribution (1) hypoxic pulmonary vasoconstriction matches perfusion to ventilation; (2) hypoxic pulmonary vasoconstriction homogenizes regional alveolar-capillary oxygen flux; and (3) hypoxic pulmonary vasoconstriction increases whole-lobe oxygen uptake by improving ventilation-perfusion matching.

Development of In-Browser Simulators for Medical Education: Introduction of a Novel Software Toolchain.

BACKGROUND: Simulators used in teaching are interactive applications comprising a mathematical model of the system under study and a graphical user interface (GUI) that allows the user to control the model inputs and visualize the model results in an intuitive and educational way. Well-designed simulators promote active learning, enhance problem-solving skills, and encourage collaboration and small group discussion. However, creating simulators for teaching purposes is a challenging process that requires many contributors including educators, modelers, graphic designers, and programmers. The availability of a toolchain of user-friendly software tools for building simulators can facilitate this complex task. OBJECTIVE: This paper aimed to describe an open-source software toolchain termed Bodylight.js that facilitates the creation of browser-based client-side simulators for teaching purposes, which are platform independent, do not require any installation, and can work offline. The toolchain interconnects state-of-the-art modeling tools with current Web technologies and is designed to be resilient to future changes in the software ecosystem. METHODS: We used several open-source Web technologies, namely, WebAssembly and JavaScript, combined with the power of the Modelica modeling language and deployed them on the internet with interactive animations built using Adobe Animate. RESULTS: Models are implemented in the Modelica language using either OpenModelica or Dassault Systèmes Dymola and exported to a standardized Functional Mock-up Unit (FMU) to ensure future compatibility. The C code from the FMU is further compiled to WebAssembly using Emscripten. Industry-standard Adobe Animate is used to create interactive animations. A new tool called Bodylight.js Composer was developed for the toolchain that enables one to create the final simulator by composing the GUI using animations, plots, and control elements in a drag-and-drop style and binding them to the model variables. The resulting simulators are stand-alone HyperText Markup Language files including JavaScript and WebAssembly. Several simulators for physiology education were created using the Bodylight.js toolchain and have been received with general acclaim by teachers and students alike, thus validating our approach. The Nephron, Circulation, and Pressure-Volume Loop simulators are presented in this paper. Bodylight.js is licensed under General Public License 3.0 and is free for anyone to use. CONCLUSIONS: Bodylight.js enables us to effectively develop teaching simulators. Armed with this technology, we intend to focus on the development of new simulators and interactive textbooks for medical education. Bodylight.js usage is not limited to developing simulators for medical education and can facilitate the development of simulators for teaching complex topics in a variety of different fields.

A simulation study of left ventricular decompression using a double lumen arterial cannula prototype during a veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation can be vital to support patients in severe or rapidly progressing cardiogenic shock. In cases of left ventricular distension, left ventricular decompression during veno-arterial extracorporeal membrane oxygenation may be a crucial factor influencing the patient outcome. Application of a double lumen arterial cannula for a left ventricular unloading is an alternative, straightforward method for left ventricular decompression during extracorporeal membrane oxygenation in a veno-arterial configuration. OBJECTIVES: The purpose of this article is to use a mathematical model of the human adult cardiovascular system to analyze the left ventricular function of a patient in cardiogenic shock supported by veno-arterial extracorporeal membrane oxygenation with and without the application of left ventricular unloading using a novel double lumen arterial cannula. METHODS: A lumped model of cardiovascular system hydraulics has been coupled with models of non-pulsatile veno-arterial extracorporeal membrane oxygenation, a standard venous cannula, and a drainage lumen of a double lumen arterial cannula. Cardiogenic shock has been induced by decreasing left ventricular contractility to 10% of baseline normal value. RESULTS: The simulation results indicate that applying double lumen arterial cannula during veno-arterial extracorporeal membrane oxygenation is associated with reduction of left ventricular end-systolic volume, end-diastolic volume, end-systolic pressure, and end-diastolic pressure. CONCLUSIONS: A double lumen arterial cannula is a viable alternative less invasive method for left ventricular decompression during veno-arterial extracorporeal membrane oxygenation. However, to allow for satisfactory extracorporeal membrane oxygenation flow, the cannula design has to be revisited.

Testing Computer Models Predicting Human Responses to a High-Salt Diet.

Recently, mathematical models of human integrative physiology, derived from Guyton's classic 1972 model of the circulation, have been used to investigate potential mechanistic abnormalities mediating salt sensitivity and salt-induced hypertension. We performed validation testing of 2 of the most evolved derivatives of Guyton's 1972 model, Quantitative Cardiovascular Physiology-2005 and HumMod-3.0.4, to determine whether the models accurately predict sodium balance and hemodynamic responses of normal subjects to increases in salt intake within the real-life range of salt intake in humans. Neither model, nor the 1972 Guyton model, accurately predicts the usual changes in sodium balance, cardiac output, and systemic vascular resistance that normally occur in response to clinically realistic increases in salt intake. Furthermore, although both contemporary models are extensions of the 1972 Guyton model, testing revealed major inconsistencies between model predictions with respect to sodium balance and hemodynamic responses of normal subjects to short-term and long-term salt loading. These results demonstrate significant limitations with the hypotheses inherent in the Guyton models regarding the usual regulation of sodium balance, cardiac output, and vascular resistance in response to increased salt intake in normal salt-resistant humans. Accurate understanding of the normal responses to salt loading is a prerequisite for accurately establishing abnormal responses to salt loading. Accordingly, the present results raise concerns about the interpretation of studies of salt sensitivity with the various Guyton models. These findings indicate a need for continuing development of alternative models that incorporate mechanistic concepts of blood pressure regulation fundamentally different from those in the 1972 Guyton model and its contemporary derivatives.

Modern and traditional approaches combined into an effective gray-box mathematical model of full-blood acid-base.

BACKGROUND: The acidity of human body fluids, expressed by the pH, is physiologically regulated in a narrow range, which is required for the proper function of cellular metabolism. Acid-base disorders are common especially in intensive care, and the acid-base status is one of the vital clinical signs for the patient management. Because acid-base balance is connected to many bodily processes and regulations, complex mathematical models are needed to get insight into the mixed disorders and to act accordingly. The goal of this study is to develop a full-blood acid-base model, designed to be further integrated into more complex human physiology models. RESULTS: We have developed computationally simple and robust full-blood model, yet thorough enough to cover most of the common pathologies. Thanks to its simplicity and usage of Modelica language, it is suitable to be embedded within more elaborate systems. We achieved the simplification by a combination of behavioral Siggaard-Andersen's traditional approach for erythrocyte modeling and the mechanistic Stewart's physicochemical approach for plasma modeling. The resulting model is capable of providing variations in arterial pCO2, base excess, strong ion difference, hematocrit, plasma protein, phosphates and hemodilution/hemoconcentration, but insensitive to DPG and CO concentrations. CONCLUSIONS: This study presents a straightforward unification of Siggaard-Andersen's and Stewart's acid-base models. The resulting full-blood acid-base model is designed to be a core part of a complex dynamic whole-body acid-base and gas transfer model.

Surviving sepsis--a 3D integrative educational simulator.

Computer technology offers greater educational possibilities, notably simulation and virtual reality. This paper presents a technology which serves to integrate multiple modalities, namely 3D virtual reality, node-based simulator, Physiomodel explorer and explanatory physiological simulators employing Modelica language and Unity3D platform. This emerging tool chain should allow the authors to concentrate more on educational content instead of application development. The technology is demonstrated through Surviving sepsis educational scenario, targeted on Microsoft Windows Store platform.

Experiences in teaching of modeling and simulation with emphasize on equation-based and acausal modeling techniques.

This work introduces experiences of teaching modeling and simulation for graduate students in the field of biomedical engineering. We emphasize the acausal and object-oriented modeling technique and we have moved from teaching block-oriented tool MATLAB Simulink to acausal and object oriented Modelica language, which can express the structure of the system rather than a process of computation. However, block-oriented approach is allowed in Modelica language too and students have tendency to express the process of computation. Usage of the exemplar acausal domains and approach allows students to understand the modeled problems much deeper. The causality of the computation is derived automatically by the simulation tool.