Replacement of animal models of cardiac arrest and resuscitation strategies using a computer simulation

This doctoral thesis explores cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) from a multidisciplinary perspective, with a focus on three main objectives: enhancing the Interdisciplinary Collaboration in Systems Medicine (ICSM) simulation suite, investigating the pathophysiology of CA, and proposing an alternative to animal models in CA and CPR research. The ICSM simulation suite was significantly improved, with additions such as a thoracic model for chest compressions, multiple organ tissue compartments, a vasculature equation accounting for resistance changes, circulatory transport delays, retrograded blood flow during CPR, and respiratory and cardiovascular control mechanisms. Utilizing the enhanced ICSM simulation suite, a series of studies were conducted to examine various aspects of CPR strategies, all with the aim of improving resuscitation outcomes. These studies encompassed investigations into the impact of positive end-expiratory pressure (PEEP) on cardiac output during CPR, the effects of chest compression rate, depth, and duty cycle, the influence of the precipitating aetiology on CPR strategy optimization, and the comparison of personalized CPR strategies to current guidelines. The research also quantitatively identified the effect of CPR parameters on cardiac output, with end compression force and positive end expiratory pressure emerging as significant contributors. The validation of the ICSM simulation suite thoracic model using individual haemodynamic recordings of a patient undergoing CPR demonstrated its capacity to simulate individualized patient data for retrospective identification of optimized CPR protocols. These outcomes collectively emphasize the potential of computational models, particularly the ICSM simulation suite, to revolutionize CA and CPR research by providing humane, informative, and personalized alternatives to traditional animal models. The findings of this research suggest that the ICSM simulation suite offers a valuable alternative to animal models in the study of CA and CPR. This computational model allows for the simulation and investigation of personalized CPR strategies, which can be tailored to individual patients' need

Replacement of animal models of cardiac arrest and resuscitation strategies using a computer simulation

This doctoral thesis explores cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) from a multidisciplinary perspective, with a focus on three main objectives: enhancing the Interdisciplinary Collaboration in Systems Medicine (ICSM) simulation suite, investigating the pathophysiology of CA, and proposing an alternative to animal models in CA and CPR research. The ICSM simulation suite was significantly improved, with additions such as a thoracic model for chest compressions, multiple organ tissue compartments, a vasculature equation accounting for resistance changes, circulatory transport delays, retrograded blood flow during CPR, and respiratory and cardiovascular control mechanisms. Utilizing the enhanced ICSM simulation suite, a series of studies were conducted to examine various aspects of CPR strategies, all with the aim of improving resuscitation outcomes. These studies encompassed investigations into the impact of positive end-expiratory pressure (PEEP) on cardiac output during CPR, the effects of chest compression rate, depth, and duty cycle, the influence of the precipitating aetiology on CPR strategy optimization, and the comparison of personalized CPR strategies to current guidelines. The research also quantitatively identified the effect of CPR parameters on cardiac output, with end compression force and positive end expiratory pressure emerging as significant contributors. The validation of the ICSM simulation suite thoracic model using individual haemodynamic recordings of a patient undergoing CPR demonstrated its capacity to simulate individualized patient data for retrospective identification of optimized CPR protocols. These outcomes collectively emphasize the potential of computational models, particularly the ICSM simulation suite, to revolutionize CA and CPR research by providing humane, informative, and personalized alternatives to traditional animal models. The findings of this research suggest that the ICSM simulation suite offers a valuable alternative to animal models in the study of CA and CPR. This computational model allows for the simulation and investigation of personalized CPR strategies, which can be tailored to individual patients' need

Nonlinear dynamics and modeling of heart and brain signals

Ph.DDOCTOR OF PHILOSOPH

Development, characterization and evaluation of advanced therapies for the treatment of cardiac pathologies

Cardiovascular diseases (CVDs) are the leading cause of disease burden and mortality in the world, as well as a major cause of disability and health care costs. With the average lifespan of the human population continuously increasing, it is expected that the problem of CVDs will only continue to grow in the following years. Current pharmacological treatments for age-associated cardiac pathologies such as heart failure and atrial fibrillation present severe clinical efficacy and safety problems and are not regarded as definitive cures. This makes it necessary to develop new treatment strategies that target the involved molecular pathways and trigger endogenous reparative responses. Contrary to current molecular treatments, advanced therapy medicinal products (ATMPs) such as stem cells, extracellular vesicles (EVs) and biomaterials such as hydrogels could have the potential to treat cardiac aging-associated pathologies from a more fundamental level. However, many problems and unknowns still need to be solved before they can reach the clinical scenario. Some of the most highlighted limitations we focus on in this work are: (i) the lack of deep understanding of their mechanism of action (MoA), (ii) their large variability and lack of standardization (including inadequate potency tests) and (iii) low in vivo retention at the site of interest. Therefore, the main objective of this thesis is to develop, characterize and evaluate advanced therapies for the treatment of cardiac pathologies solving some of their current limitations to enhance their therapeutic potential. To achieve this aim, we first focus on improving standardization and development of potency assays. We describe the main characteristics and challenges for a cell therapy based potency test in the cardiovascular field and we review and propose different types of assays that could be taken into consideration based on the product’s expected MoA and the target cardiovascular disease. Secondly, as cardiosphere-derived cells (CDCs) and their secreted EVs (CDC-EVs) have previously reported to have anti-senescent effects and this is considered important in aging-related cardiac diseases, we explore potential predictors of rejuvenating potency with a special focus on the chronological age of the CDC-donors and CDC-senescence, among others. Multiple in vitro tests allow us to conclude that more than cell particular biological markers or characteristics, the cell bioactivity relative to the expected MoA should be a better predictor for the ATMP potency. Thus, we evaluate if the in vitro anti-senescent and pro-angiogenic effect of the CDC-EVs, scored with a matrix assay, can be used to predict the in vivo potency of the CDC-EVs in an animal model of cardiac aging. Our results show that EVs classified in vitro as potent with the matrix assay have more cardiac reparative potential in vivo than EVs classified as non-potent. After further validation, the matrix assay proposed here could be a suitable in vitro potency test for discerning suitable allogenic biological products in the cardiac aging clinical scenario. Next, with the purpose of improving EV retention at the site of interest, we develop an optimized product combining hydrogels from cardiac extracellular matrix (cECM), polyethylene glycol and EVs to overcome some of their individual limitations: long gelation time of the cECM and poor retention of the EVs. We conclude that the combined product rapidly gels at physiological temperature and presents improved mechanical properties while maintaining the injectability, the biodegradability, and the bioactivity of its individual components. In addition, it serves to better retain the EVs on-site in vivo. Finally, we explore the electrophysiological modifications induced by CDC-EVs on arrhythmogenic tissue to better understand the mechanisms behind their antiarrhythmic effect. We found that CDC-EVs reduce spontaneous activation complexity and increase conduction velocity of cardiomyocytes leading to a less arrhythmogenic profile. If validated in other cellular models, CDC-EVs may be used specifically as antiarrhythmic agents in a wide range of cardiac pathologies. Although future work should aim to further validate these results both at preclinical and clinical level, these findings together partially overcome some of the main challenges for the therapeutic use of cellular therapies and open a new horizon for the treatment of cardiac-aging related pathologies, some still considered as unmet medical needs.Programa de Doctorado en Ciencia y Tecnología Biomédica por la Universidad Carlos III de MadridPresidenta: Eva Delpón Mosquera.- Secretaria: Marta García Díez.- Vocal: Javier Bermejo Thoma

Stem Cell Research on Cardiology

Even today, cardiovascular diseases are the main cause of death worldwide, and therapeutic approaches are very restricted. Due to the limited regenerative capabilities of terminally differentiated cardiomyocytes post injury, new strategies to treat cardiac patients are urgently needed. Post myocardial injury, resident fibroblasts begin to generate the extracellular matrix, resulting in fibrosis, and finally, cardiac failure. Recently, preclinical investigations and clinical trials raised hope in stem cell-based approaches, to be an effective therapy option for these diseases. So far, several types of stem cells have been identified to be promising candidates to be applied for treatment: cardiac progenitor cells, bone marrow derived stem cells, embryonic and induced pluripotent stem cells, as well as their descendants. Furthermore, the innovative techniques of direct cardiac reprogramming of cells offered promising options for cardiovascular research, in vitro and in vivo. Hereby, the investigation of underlying and associated mechanisms triggering the therapeutic effects of stem cell application is of particular importance to improve approaches for heart patients. This Special Issue of Cells provides the latest update in the rapidly developing field of regenerative medicine in cardiology

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

Biomedical Signal and Image Processing

Written for senior-level and first year graduate students in biomedical signal and image processing, this book describes fundamental signal and image processing techniques that are used to process biomedical information. The book also discusses application of these techniques in the processing of some of the main biomedical signals and images, such as EEG, ECG, MRI, and CT. New features of this edition include the technical updating of each chapter along with the addition of many more examples, the majority of which are MATLAB based