Aspects of Pacemakers

Outstanding steps forward were made in the last decades in terms of identification of endogenous pacemakers and the exploration of their controllability. New "artifical" devices were developed and are now able to do much more than solely pacemaking of the heart. In this book different aspects of pacemaker - functions and interactions, in various organ systems were examined. In addition, various areas of application and the potential side effects and complications of the devices were discussed

Fluid-electro-mechanical model of the human heart for supercomputers

The heart is a complex system. From the transmembrane cell activity to the spatial organization in helicoidal fibers, it includes several spatial and temporal scales. The heart muscle is surrounded by two main tissues that modulate how it deforms: the pericardium and the blood. The former constrains the epicardial surface and the latter exerts a force in the endocardium. The main function of this peculiar muscle is to pump blood to the pulmonary and systemic circulations. In this way, solid dynamics of the heart is as important as the induced fluid dynamics. Despite the work done in computational research of multiphysics heart modelling, there is no reference of a tightly-coupled scheme that includes electrophysiology, solid and fluid mechanics in a whole human heart. In this work, we propose, develop and test a fluid-electro-mechanical model of the human heart. To start, the heartbeat phenomenon is disassembled in the different composing problems. The first building block is the electrical activity of the myocytes, that induces the mechanical deformation of the myocardium. The contraction of the muscle reduces the intracavitary space, that pushes out the contained blood. At the same time, the inertia, pressure and viscous stresses in this fluid exerts a force on the solid wall. In this way, we can understand the heart as a fluid-electro-mechanical problem. All the models are implemented in Alya, the Barcelona Supercomputing Center simulation software. A multi-code approach is used, splitting the problem in a solid and a fluid domain. In the former, electrophysiology coupled with solid mechanics are solved. In the later, fluid dynamics in an arbitrary Lagrangian-Eulerian domain are computed. The equations are spatially discretized using the finite element method and temporally discretized using finite differences. Facilitated by the multi-code approach, a novel high performance quasi-Newton method is developed to deal with the intrinsic issues of fluid-structure interaction problems in iomechanics. All the schemes are optimized to run in massively parallel computers. A wide range of experiments are shown to validate, test and tune the numerical model. The different hypothesis proposed — as the critical effect of the atrium or the presence of pericardium — are also tested in these experiments. Finally, a normal heartbeat is simulated and deeply analyzed. This healthy computational heart is first diseased with a left bundle branch block. After this, its function is restored simulating a cardiac resynchronization therapy. Then, a third grade atrioventricular block is simulated in the healthy heart. In this case, the pathologic model is treated with a minimally invasive leadless intracardiac pacemaker. This requires to include the device in the geometrical description of the problem, solve the structural problem with the tissue, and the fluid-structure interaction problem with the blood. As final experiment, we test the parallel performance of the coupled solver. In the cases mentioned above, the results are qualitatively compared against experimental measurements, when possible. Finally, a first glance in a coupled fluid-electro-mechanical cardiovascular system is shown. This model is build adding a one dimensional model of the arterial network created by the Laboratório Nacional de Computação Científica in Petropolis, Brasil. Despite the artificial geometries used, the outflow curves are comparable with physiological observations. The model presented in this thesis is a step towards the virtual human heart. In a near future computational models like the presented in this thesis will change how pathologies are understood and treated, and the way biomedical devices are designed.El corazón es un sistema complejo. Desde la actividad celular hasta la organización espacial en fibras helicoidales, incluye gran cantidad de escalas espaciales y temporales. El corazón está rodeado principalmente por dos tejidos que modulan su deformación: el pericardio y la sangre. El primero restringe el movimiento del epicardio, mientras el segundo ejerce fuerza sobre el endocardio. La función principal de este músculo es bombear sangre a la circulación sistémica y a la pulmonar. Así, la deformación del miocardio es tan importante como la fluidodinámica inducida. Al día de hoy, solo se han propuesto modelos parciales del corazón. Ninguno de los modelos publicados resuelve electrofisiología, mecánica del sólido, y dinámica de fluidos en una geometría completa del corazón. En esta tesis, proponemos, desarrollamos y probamos un modelo fluido -electro -mecánico del corazón. Primero, el problema del latido cardíaco es descompuesto en los distintos subproblemas. El primer bloque componente es la actividad eléctrica de los miocitos, que inducen la deformación mecánica del miocardio. La contratación de este músculo, reduce el espacio intracavitario, que empuja la sangre contenida. Al mismo tiempo, la inercia, presión y fuerzas viscosas del fluido inducen una presión sobre la pared del sólido. De esta manera, podemos entender el latido cardíaco como un problema fluido-electro-mecánico. Los modelos son implementados en Alya, el software de simulación del Barcelona Supercomputing Center. Se utiliza un diseño multi-código, separando el problema según el dominio en sólido y fluido. En el primero, se resuelve electrofisiología acoplado con mecánica del sólido. En el segundo, fluido dinámica en un dominio arbitrario Lagrangiano-Euleriano. Las ecuaciones son discretizadas espacial y temporalmente utilizando elementos finitos y diferencias finitas respectivamente. Facilitado por el diseño multi-codigo, se desarrolló un novedoso método quasi-Newton de alta performance, pensado específicamente para lidiar con los problemas intrínsecos de interacción fluido-estructura en biomecánica. Todos los esquemas fueron optimizados para correr en ordenadores masivamente paralelos.Se presenta un amplio espectro de experimentos con el fin de validar, probar y ajustar el modelo numérico. Las diferentes hipótesis propuestas tales como el efecto producido por la presencia de las aurículas o el pericardio son también demostradas en estos experimentos. Finalmente un latido normal es simulado y sus resultados son analizados con profundidad. El corazón computacional sano es, primeramente enfermado de un bloqueo de rama izquierda. Posteriormente se restaura la función normal mediante la terapia de resincronización cardíaca. Luego se afecta al corazón de un bloqueo atrioventricular de tercer grado. Esta patología es tratada mediante la implantación de un marcapasos intracardíaco. Para esto, se requiere incluir el dispositivo en la descripción geométrica, resolver el problema estructural con el tejido y la interacción fluido-estructura con la sangre. Como experimento numérico final, se prueba el desempeño paralelo del modelo acoplado.Finalmente, se muestran resultados preliminares para un modelo fluido-electro-mecánico del sistema cardiovascular. Este modelo se construye agregando un modelo unidimensional del árbol arterial. A pesar de las geometrías artificiales usadas, la curva de flujo en la raíz aórtica es comparable con observaciones experimentales. El modelo presentado aquí representa un avance hacia el humano virtual. En un futuro, modelos similares, cambiarán la forma en la que se entienden y tratan las enfermedades y la forma en la que los dispositivos biomédicos son diseñados.Postprint (published version

On the Modeling of Transcatheter Therapies for the Aortic and Mitral Valves: A Review

Transcatheter aortic valve replacement (TAVR) has become a milestone for the management of aortic stenosis in a growing number of patients who are unfavorable candidates for surgery. With the new generation of transcatheter heart valves (THV), the feasibility of transcatheter mitral valve replacement (TMVR) for degenerated mitral bioprostheses and failed annuloplasty rings has been demonstrated. In this setting, computational simulations are modernizing the preoperative planning of transcatheter heart valve interventions by predicting the outcome of the bioprosthesis interaction with the human host in a patient-specific fashion. However, computational modeling needs to carry out increasingly challenging levels including the verification and validation to obtain accurate and realistic predictions. This review aims to provide an overall assessment of the recent advances in computational modeling for TAVR and TMVR as well as gaps in the knowledge limiting model credibility and reliability

Advanced intelligent control and optimization for cardiac pacemaker systems

Since cardiovascular diseases are major causes of morbidity and mortality in the developed countries and the number one cause of death in the United States, their accurate diagnosis and effective treatment via advanced cardiac pacemaker systems have become very important. Intelligent control and optimization of the pacemakers are significant research subjects. Serious but infrequently occurring arrhythmias are difficult to diagnose. The use of electrocardiogram (ECG) waveform only cannot exactly distinguish between deadly abnormalities and temporary arrhythmias. Thus, this work develops a new method based on frequency entrainment to analyze pole-zero characteristics of the phase error between abnormal ECG and entrained Yanagihara, Noma, and Irisawa (YNI)-response. The thresholds of poles and zeros to diagnose deadly bradycardia and tachycardia are derived, respectively, for the first time. For bradycardia under different states, a fuzzy proportional-integral-derivative (FPID) controller for dual- sensor cardiac pacemaker systems is designed. It can automatically control the heart rate to accurately track a desired preset profile. Through comparing with the conventional algorithm, FPID provides a more suitable control strategy for offering better adaptation of the heart rate, in order to fulfill the patient\u27s physiological needs. This novel control method improves the robustness and performance of a pacemaker system significantly. Higher delivered energy for stimulation may cause higher energy consumption in pacemakers and accelerated battery depletion. Hence, this work designs an optimal single-pulse stimulus to treat sudden cardiac arrest, while minimizing the pulse amplitude and releasing stimulus pain. Moreover, it derives the minimum pulse amplitude for successful entrainment. The simulation results confirm that the optimal single-pulse is effective to induce rapid response of sudden cardiac arrest for heartbeat recovery, while a significant reduction in the delivered energy is achieved. The study will be helpful for not only better diagnosis and treatment of cardiovascular diseases but also improving the performance of pacemaker systems

Diabetes increases mortality after myocardial infarction by oxidizing CaMKII

Diabetes increases oxidant stress and doubles the risk of dying after myocardial infarction, but the mechanisms underlying increased mortality are unknown. Mice with streptozotocin-induced diabetes developed profound heart rate slowing and doubled mortality compared with controls after myocardial infarction. Oxidized Ca(2+)/calmodulin-dependent protein kinase II (ox-CaMKII) was significantly increased in pacemaker tissues from diabetic patients compared with that in nondiabetic patients after myocardial infarction. Streptozotocin-treated mice had increased pacemaker cell ox-CaMKII and apoptosis, which were further enhanced by myocardial infarction. We developed a knockin mouse model of oxidation-resistant CaMKIIδ (MM-VV), the isoform associated with cardiovascular disease. Streptozotocin-treated MM-VV mice and WT mice infused with MitoTEMPO, a mitochondrial targeted antioxidant, expressed significantly less ox-CaMKII, exhibited increased pacemaker cell survival, maintained normal heart rates, and were resistant to diabetes-attributable mortality after myocardial infarction. Our findings suggest that activation of a mitochondrial/ox-CaMKII pathway contributes to increased sudden death in diabetic patients after myocardial infarction

Current Issues and Recent Advances in Pacemaker Therapy

Patients with implanted pacemakers or defibrillators are frequently encountered in various healthcare settings. As these devices may be responsible for, or contribute to a variety of clinically significant issues, familiarity with their function and potential complications facilitates patient management. This book reviews several clinically relevant issues and recent advances of pacemaker therapy: implantation, device follow-up and management of complications. Innovations and research on the frontiers of this technology are also discussed as they may have wider utilization in the future. The book should provide useful information for clinicians involved in the management of patients with implanted antiarrhythmia devices and researchers working in the field of cardiac implants

Device, Method, and Algorithm to Assess Changes in Cardiac Output via Intracardiac Impedance Monitoring

Cardiac output, the volume of blood pumped by the heart over time, is a powerful clinical metric used by physicians to assess overall cardiac health and patient well-being. However, current cardiac output estimation methods are typically invasive, time-consuming, expensive, or some combination of all three. Patients that receive artificial cardiac pacemaker devices are particularly susceptible to cardiac dysfunction and often require long-term cardiac monitoring support. This thesis proposes a novel cardiac output monitoring solution which leverages an implantable intracardiac medical device. The principles of traditional impedance cardiography, an established cardiac output monitoring technique in practice for over fifty years, have been adapted to incorporate a leadless artificial cardiac pacemaker, an implantable medical device contained entirely within the heart. This novel method, colloquially referred to as Z-Cardio, monitors time-varying intracardiac impedance modulation to assess changes in cardiac output. In this study, technologies both old and new are synthesized to produce a novel and effective method of monitoring a critical metric of cardiac health

Modelling bio-compatible and bio-integrative medical devices

International audienceDeveloping and producing medical devices and healthcare systems is a crucial issue, both for the economy and for providing safe advances in healthcare delivery. We propose a taxonomy of medical human machine systems and we define classes of healthcare applications for identifying a number of approaches and to overcome difficulties of bio-compatibility and bio-integration. Our aim is to demonstrate how medical devices design, and more generally human-machine system concepts and epistemology, depend on our skills to think and conceptualize generally human system integration. We claim that it is necessary to reclaim these concepts for ensuring correct by construction medical devices bio-compatibility and biointegrative properties from the early stage of the design process

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