Heart Rhythm Insights Into Structural Remodeling in Atrial Tissue: Timed Automata Approach

The heart rhythm of a person following heart transplantation (HTX) is assumed to display an intrinsic cardiac rhythm because it is significantly less influenced by the autonomic nervous system—the main source of heart rate variability in healthy people. Therefore, such a rhythm provides evidence for arrhythmogenic processes developing, usually silently, in the cardiac tissue. A model is proposed to simulate alterations in the cardiac tissue and to observe the effects of these changes on the resulting heart rhythm. The hybrid automata framework used makes it possible to represent reliably and simulate efficiently both the electrophysiology of a cardiac cell and the tissue organization. The curve fitting method used in the design of the hybrid automaton cycle follows the well-recognized physiological phases of the atrial myocyte membrane excitation. Moreover, knowledge of the complex architecture of the right atrium, the ability of the almost free design of intercellular connections makes the automata approach the only one possible. Two particular aspects are investigated: impairment of the impulse transmission between cells and structural changes in intercellular connections. The first aspect models the observed fatigue of cells due to specific cardiac tissue diseases. The second aspect simulates the increase in collagen deposition with aging. Finally, heart rhythms arising from the model are validated with the sinus heart rhythms recorded in HTX patients. The modulation in the impairment of the impulse transmission between cells reveals qualitatively the abnormally high heart rate variability observed in patients living long after HTX

High-Confidence Medical Device Software Development

The design of bug-free and safe medical device software is challenging, especially in complex implantable devices. This is due to the device\u27s closed-loop interaction with the patient\u27s organs, which are stochastic physical environments. The life-critical nature and the lack of existing industry standards to enforce software validation make this an ideal domain for exploring design automation challenges for integrated functional and formal modeling with closed-loop analysis. The primary goal of high-confidence medical device software is to guarantee the device will never drive the patient into an unsafe condition even though we do not have complete understanding of the physiological plant. There are two major differences between modeling physiology and modeling man-made systems: first, physiology is much more complex and less well-understood than man-made systems like cars and airplanes, and spans several scales from the molecular to the entire human body. Secondly, the variability between humans is orders of magnitude larger than that between two cars coming off the assembly line. Using the implantable cardiac pacemaker as an example of closed-loop device, and the heart as the organ to be modeled, we present several of the challenges and early results in model-based device validation. We begin with detailed timed automata model of the pacemaker, based on the specifications and algorithm descriptions from Boston Scientific. For closed-loop evaluation, a real-time Virtual Heart Model (VHM) has been developed to model the electrophysiological operation of the functioning and malfunctioning (i.e., during arrhythmia) hearts. By extracting the timing properties of the heart and pacemaker device, we present a methodology to construct timed-automata models for formal model checking and functional testing of the closed-loop system. The VHM\u27s capability of generating clinically-relevant response has been validated for a variety of common arrhythmias. Based on a set of requirements, we describe a framework of Abstraction Trees that allows for interactive and physiologically relevant closed-loop model checking and testing for basic pacemaker device operations such as maintaining the heart rate, atrial-ventricle synchrony and complex conditions such as avoiding pacemaker-mediated tachycardia. Through automatic model translation of abstract models to simulation-based testing and code generation for platform-level testing, this model-based design approach ensures the closed-loop safety properties are retained through the design toolchain and facilitates the development of verified software from verified models. This system is a step toward a validation and testing approach for medical cyber-physical systems with the patient-in-the-loop

From Verified Models to Verified Code for Safe Medical Devices

Medical devices play an essential role in the care of patients around the world, and can have a life-saving effect. An emerging category of autonomous medical devices like implantable pacemakers and implantable cardioverter defibrillators (ICD) diagnose conditions of the patient and autonomously deliver therapies. Without trained professionals in the loop, the software component of autonomous medical devices is responsible for making critical therapeutic decisions, which pose a new set of challenges to guarantee patient safety. As regulation effort to guarantee patient safety, device manufacturers are required to submit evidence for the safety and efficacy of the medical devices before they can be released to the market. Due to the closed-loop interaction between the device and the patient, the safety and efficacy of autonomous medical devices must ultimately be evaluated within their physiological context. Currently the primary closed-loop validation of medical devices is in form of clinical trials, in which the devices are evaluated on real patients. Clinical trials are expensive and expose the patients to risks associated with untested devices. Clinical trials are also conducted after device development, therefore issues found during clinical trials are expensive to fix. There is urgent need for closed-loop validation of autonomous medical devices before the devices are used in clinical trials. In this thesis, I used implantable cardiac devices to demonstrate the applications of model-based approaches during and after device development to provide confidence towards the safety and efficacy of the devices. A heart model structure is developed to mimic the electrical behaviors of the heart in various heart conditions. The heart models created with the model structure are capable of interacting with implantable cardiac devices in closed-loop and can provide physiological interpretations for a large variety of heart conditions. With the heart models, I demonstrated that closed-loop model checking is capable of identifying known and unknown safety violations within the pacemaker design. More importantly, I developed a framework to choose the most appropriate heart models to cover physiological conditions that the pacemaker may encounter, and provide physiological context to counter-examples returned by the model checker. A model translation tool UPP2SF is then developed to translate the pacemaker design in UPPAAL to Stateflow, and automatically generated to C code. The automated and rigorous translation ensures that the properties verified during model checking still hold in the implementation, which justifies the model checking effort. Finally, the devices are evaluated with a virtual patient cohort consists of a large number of heart models before evaluated in clinical trials. These in-silico pre-clinical trials provide useful insights which can be used to increase the success rate of a clinical trial. The work in this dissertation demonstrated the importance and challenges to represent physiological behaviors during closed-loop validation of autonomous medical devices, and demonstrated the capability of model-based approaches to provide safety and efficacy evidence during and after device development

Stories from different worlds in the universe of complex systems: A journey through microstructural dynamics and emergent behaviours in the human heart and financial markets

A physical system is said to be complex if it exhibits unpredictable structures, patterns or regularities emerging from microstructural dynamics involving a large number of components. The study of complex systems, known as complexity science, is maturing into an independent and multidisciplinary area of research seeking to understand microscopic interactions and macroscopic emergence across a broad spectrum systems, such as the human brain and the economy, by combining specific modelling techniques, data analytics, statistics and computer simulations. In this dissertation we examine two different complex systems, the human heart and financial markets, and present various research projects addressing specific problems in these areas. Cardiac fibrillation is a diffuse pathology in which the periodic planar electrical conduction across the cardiac tissue is disrupted and replaced by fast and disorganised electrical waves. In spite of a century-long history of research, numerous debates and disputes on the mechanisms of cardiac fibrillation are still unresolved while the outcomes of clinical treatments remain far from satisfactory. In this dissertation we use cellular automata and mean-field models to qualitatively replicate the onset and maintenance of cardiac fibrillation from the interactions among neighboring cells and the underlying topology of the cardiac tissue. We use these models to study the transition from paroxysmal to persistent atrial fibrillation, the mechanisms through which the gap-junction enhancer drug Rotigaptide terminates cardiac fibrillation and how focal and circuital drivers of fibrillation may co-exist as projections of transmural electrical activities. Financial markets are hubs in which heterogeneous participants, such as humans and algorithms, adopt different strategic behaviors to exchange financial assets. In recent decades the widespread adoption of algorithmic trading, the electronification of financial transactions, the increased competition among trading venues and the use of sophisticated financial instruments drove the transformation of financial markets into a global and interconnected complex system. In this thesis we introduce agent-based and state-space models to describe specific microstructural dynamics in the stock and foreign exchange markets. We use these models to replicate the emergence of cross-currency correlations from the interactions between heterogeneous participants in the currency market and to disentangle the relationships between price fluctuations, market liquidity and demand/supply imbalances in the stock market.Open Acces

Computer-Aided Clinical Trials For Medical Devices

Life-critical medical devices require robust safety and efficacy to treat patient populations with potentially large patient heterogeneity. Today, the de facto standard for evaluating medical devices is the randomized controlled trial. However, even after years of device development many clinical trials fail. For example, in the Rhythm ID Goes Head to Head Trial (RIGHT) the risk for inappropriate therapy by implantable cardioverter defibrillators (ICDs) actually increased relative to control treatments. With recent advances in physiological modeling and devices incorporating more complex software components, population-level device outcomes can be obtained with scalable simulations. Consequently, there is a need for data-driven approaches to provide early insight prior to the trial, lowering the cost of trials using patient and device models, and quantifying the robustness of the outcome. This work presents a clinical trial modeling and statistical framework which utilizes simulation to improve the evaluation of medical device software, such as the algorithms in ICDs. First, a method for generating virtual cohorts using a physiological simulator is introduced. Next, we present our framework which combines virtual cohorts with real data to evaluate the efficacy and allows quantifying the uncertainty due to the use of simulation. Results predicting the outcome of RIGHT and improving statistical power while reducing the sample size are shown. Finally, we improve device performance with an approach using Bayesian optimization. Device performance can degrade when deployed to a general population despite success in clinical trials. Our approach improves the performance of the device with outcomes aligned with the MADIT-RIT clinical trial. This work provides a rigorous approach towards improving the development and evaluation of medical treatments

Modeling Human Atrial Patho-Electrophysiology from Ion Channels to ECG - Substrates, Pharmacology, Vulnerability, and P-Waves

Half of the patients suffering from atrial fibrillation (AF) cannot be treated adequately, today. This thesis presents multi-scale computational methods to advance our understanding of patho-mechanisms, to improve the diagnosis of patients harboring an arrhythmogenic substrate, and to tailor therapy. The modeling pipeline ranges from ion channels on the subcellular level up to the ECG on the body surface. The tailored therapeutic approaches carry the potential to reduce the burden of AF

Modeling Human Atrial Patho-Electrophysiology from Ion Channels to ECG - Substrates, Pharmacology, Vulnerability, and P-Waves

Half of the patients suffering from atrial fibrillation (AF) cannot be treated adequately, today. This book presents multi-scale computational methods to advance our understanding of patho-mechanisms, to improve the diagnosis of patients harboring an arrhythmogenic substrate, and to tailor therapy. The modeling pipeline ranges from ion channels on the subcellular level up to the ECG on the body surface. The tailored therapeutic approaches carry the potential to reduce the burden of AF

Electrical modeling of myocardium and development of advanced pacing techniques

Thesis (Ph. D.)--Massachusetts Institute of Technology, Whitaker College of Health Sciences and Technology, 1998.Includes bibliographical references (p. 243-248).by Paul Aaron Belk.Ph.D

Aerospace medicine and biology: A cumulative index to the continuing bibliography of the 1973 issues

A cumulative index to the abstracts contained in Supplements 112 through 123 of Aerospace Medicine and Biology A Continuing Bibliography is presented. It includes three indexes: subject, personal author, and corporate source