Os dispositivos de assistência ventricular (DAVs) podem ser utilizados para a estabilização hemodinâmica de pacientes à espera do transplante cardíaco. Os avanços nas tecnologias e a utilização de materiais biocompatíveis vem contribuindo para o desenvolvimento de dispositivos com dimensões reduzidas e menor trauma ao sangue. A avaliação do desempenho desses dispositivos demanda a utilização de simuladores hidráulicos do sistema circulatório que reproduzam as pressões e fluxos existentes nas condições fisiológicas de interesse. Este trabalho tem como objetivo o desenvolvimento de um simulador da circulação pediátrica com ajustes automatizados de pressões. O simulador é composto por um circuito hidráulico modelando os laços sistêmico e pulmonar e um sistema microcontrolado com uma interface de usuário para medição e visualização dos fluxos e pressões ventriculares e automatização dos ajustes das pressões arteriais aórtica e pulmonar (PAo, PAP) e das pressões atriais esquerda e direita (PAE, PAD). Duas bombas pulsáteis com 15 ml de volume de ejeção são utilizadas para modelar os comportamentos mecânicos dos ventrículos esquerdo e direito. As complacências da aorta e da artéria pulmonar e as pré-cargas dos ventrículos são simuladas por câmaras com volumes ajustáveis de ar e líquido (análogo sanguíneo) utilizando uma bomba de ar. As resistências hidráulicas dos laços são ajustadas por oclusores motorizados. Os sinais instantâneos dos fluxos de entrada e saída dos DAVs e das pressões arteriais, atriais e ventriculares são obtidos por transdutores e digitalizados em um microcontrolador que comanda os oclusores e a bomba de ar. Foram desenvolvidos algoritmos para ajustes das resistências, complacências e pré-cargas. Uma interface gráfica de usuário apresenta os sinais em tempo real (ou gravados) permitindo a escolha dos parâmetros e condições de simulação. O desempenho do sistema de automatização foi avaliado nas simulações de: 1) condições definidas pelo aplicativo da interface e 2) condições fisiológicas (normal e redução na contratilidade do miocárdio). No modelo hidráulico sistêmico as pressões foram ajustadas em ambas as situações com erro máximo de 0,5% para a PAo e 5% para a PAE em aproximadamente 80 segundos. No modelo completo da circulação o erro máximo para as simulações de condições fisiológicas foi de 4% para as pressões arteriais e 5% para as atriais. Os resultados obtidos demonstram que o simulador desenvolvido permite reproduzir adequadamente as características da circulação pediátrica essenciais para a avaliação do desempenho de dispositivos de assistência mecânica. O simulador é portátil, de fácil utilização e pode ser utilizado como ferramenta didática ou para o treinamento de profissionais da saúde envolvidos em assistência a pacientes com suporte circulatório. / Ventricular assist devices (VADs) can be used for the hemodynamic stabilization of patients waiting for heart transplantation. Advances in the technologies and the use of biocompatible materials have contributed to the development of devices with reduced dimensions and blood trauma. Evaluation of the performance of these devices demands the use of hydraulic simulators of the circulatory system that reproduce pressures and flows existing in physiological conditions of interest. This work aims to develop a simulator of the pediatric circulation with automated adjustments of pressures. The simulator consists of a hydraulic circuit modeling the systemic and pulmonary branches and a microcontrolled system with a user interface for monitoring flows and ventricular pressures, and automating adjustments of aortic and pulmonary arterial pressures (AoP, PAP) and left and right atrial pressures (LAP, RAP). Two pulsatile pumps with 15 ml ejection volume are used to model the mechanical behavior of the left and right ventricles. Aortic and pulmonary arterial compliances and preloads of the ventricles are simulated by chambers with adjustable volumes of air and fluid (blood analog) using an air pump. Motorized clamps adjust the hydraulic resistances of the loops. Instantaneous signals of VAD input and output flows and of arterial, atrial and ventricular pressures are obtained by transducers and digitalized in a microcontroller that commands the clamps and the air pump. Algorithms were developed to adjust the resistances, compliances and preloads. A graphical user interface displays signals in real time (or recorded) and allows selection of simulation parameters. The performance of the automation system was tested setting pressures in two situations: 1) simulations of random conditions defined by the interface software and 2) simulations of physiological conditions (normal and low myocardial contractility). In the systemic model, the pressures were adjusted in both cases (maximum error of 0.5% for AoP and 5% for LAP) in approximately 80 seconds. In the complete model, the maximum error for simulations of physiological conditions was 4% for arterial pressures and 5% for atrial pressures. The results obtained demonstrate that the simulator developed allows mimicking the relevant features of the systemic and pulmonary branches of the circulation needed to assess the performance of mechanical circulatory assist devices. The simulator is portable, easy to operate and can be applied in teaching and training of health professionals working with mechanical circulatory support of patients.

Habilitacijos procedūrai teikiamoje mokslo darbų apžvalgoje apibendrinama Vilniaus universiteto Širdies ir kraujagyslių ligų klinikoje taikyto sunkaus širdies nepakankamumo gydymo patirtis. Įrodytas intraaortinės kontrapulsacijos balionėliu taikymo tikslingumas pacientams su dekompensuota dilatacine kardiomiopatija. Įvertintas dirbtinių skilvelių, kaip tilto į transplantaciją ar likimo terapiją efektyvumas. Nustatyta, kaip techniniai dirbtinių skilvelių pakeitimai gali daryti įtaką gydymo rezultatams. Ištirtas dirbtinių skilvelių poveikis recipiento imuninei sistemai prieš ir po transplantacijos. Apžvelgti alternatyvūs širdies transplantacijai chirurginiai gydymo metodai. Pasiūlyta originali modifikuotos labirinto operacijos technika, įvertintas jos saugumas, efektyvumas ir galimybė derinti su kitomis širdies operacijomis. Prognozuojamos ateities tendencijos labai sunkiam širdies nepakankamumui gydyti. Šiame darbe remiamasi kartu su bendraautoriais atliktų tyrimų 2001-2009 m. rezultatais. Autorius visuose apžvelgiamuose tyrimuose dalyvavo tiesiogiai, kaip padalinio, kuriame gydomi pacientai su labai sunkiu širdies nepakankamumu, vadovas ir kaip chirurgas. Remiantis publikuota medžiaga buvo daryti pranešimai ir Lietuvoje, ir užsienyje. / The experience of treatment of end-stage heart failure cumulated at Vilnius University Cardiovascular Surgery Clinic is provided for habilitation procedure. The experience of intraaortic balloon counterpulsation for the patients suffering from decompensated dilatative cardiomyopathy has been proven. The efficacy of artificial ventricular assist devices as a bridge to transplantation or destination therapy has been evaluated. The role of technical modifications of ventricular assist devices for the outcomes of treatment has been assessed. The impact of assist devices on the immune status of the patient pre- and post-transplantation has also been evaluated. The alternative methods of treatment instead of heart transplantation are reviewed. The original technique of modified maze procedure is proposed; the safety, efficacy and possibilities of combining this technique with other heart operations are assessed. The future trends for treatment of end-stage heart failure are predicted. This study is based on the investigations performed with co-authors during the period since 2001 to 2009. The author has participated directly in all reviewed investigations as the head of the department where patients suffering from end-stage heart failure are being treated and as well as a surgeon. The reports based on the published material have been presented in Lithuania and abroad.

L'insuffisance cardiaque est une maladie à grande incidence dont le traitement définitif est difficile. Les pompes d'assistance ventriculaire ont été proposées comme thérapie alternative à long terme, mais la technologie est relativement jeune et selon son design, axial ou centrifuge, le dispositif favorise soit l'hémolyse, soit la stagnation de l'écoulement sanguin. Les pompes à écoulement mixte, combinant certaines propriétés des deux types, ont été proposées comme solution intermédiaire. Pour évaluer leurs performances, nous avons effectué des comparaisons numériques entre huit pompes, deux axiales, deux centrifuges, et quatre mixtes, en employant un modèle Windkessel du système cardiovasculaire avec paramètres optimisés pour l'insuffisance cardiaque résolu avec une méthode Radau IIA3, une méthode de résolution de système d'équations différentielles ordinaires L-stable appartenant à la famille des méthodes Runge-Kutta implicites. Nos résultats semblent suggérer que les pompes d'assistance mixtes ne démontrent qu'un léger avantage comparativement aux autres types en terme de performance optimale dans le cas de l'insuffisance cardiaque, mais il faudrait effectuer plus d'essais numériques avec un modèle plus complet, entre autres avec contrôles nerveux implémentés. / Heart failure is a disease with a high incidence rate that is difficult to treat definitively. Ventricular assist devices have been proposed as alternative long-term therapeutic options, but the technology is fairly recent and depending on the design, axial or centrifugal, the device will favor hemolysis or blood flow stagnation. Mixed flow devices, which combine properties of the two previous types, have therefore been proposed as intermediate solutions. To evaluate their performance, we did a numerical comparison between eight pumps (two axial, two centrifugal, and four mixed) using a Windkessel model of the cardiovascular system with parameters optimised for heart failure and solved using a Radau IIA3 method, an L-stable method used to numerically solve systems of ordinary differential equations that belongs to the family of implicit Runge-Kutta methods. Our results suggest that in terms of optimal performance, mixed flow pumps are modest improvements over the other two types, and more tests would have to be performed using a more complete model with, among other modifications, neural control systems implemented.

This thesis presents a finite element methodology for simulating fluid–solid interactions in the left ventricle (LV) under LVAD support. The developed model was utilised to study the passive and active characteristics of ventricular function in anatomically accurate LV geometries constructed from normal and patient image data. A non–conforming ALE Navier–Stokes/finite–elasticity fluid–solid coupling system formed the core of the numerical scheme, onto which several novel numerical additions were made. These included a fictitious domain (FD) Lagrange multiplier method to capture the interactions between immersed rigid bodies and encasing elastic solids (required for the LVAD cannula), as well as modifications to the Newton–Raphson/line search algorithm (which provided a 2 to 10 fold reduction in simulation time). Additional developments involved methods for extending the model to ventricular simulations. This required the creation of coupling methods, for both fluid and solid problems, to enable the integration of a lumped parameter representation of the systemic and pulmonary circulatory networks; the implementation and tuning of models of passive and active myocardial behaviour; as well as the testing of appropriate element types for coupling non–conforming fluid– solid finite element models under high interface tractions (finding that curvilinear spatial interpolations of the fluid geometry perform best). The behaviour of the resulting numerical scheme was investigated in a series of canonical test problems and found to be convergent and stable. The FD convergence studies also found that discontinuous pressure elements were better at capturing pressure gradients across FD boundaries. The ventricular simulations focused firstly on studying the passive diastolic behaviour of the LV both with and without LVAD support. Substantially different vortical flow features were observed when LVAD outflow was included. Additionally, a study of LVAD cannula lengths, using a particle tracking algorithm to determine recirculation rates of blood within the LV, found that shorter cannulas improved the recirculation of blood from the LV apex. Incorporating myocardial contraction, the model was extended to simulate the full cardiac cycle, converging on a repeating pressure–volume loop over 2 heart beats. Studies on the normal LV geometry found that LVAD implementation restricts the recirculation of early diastolic inflow, and that fluid–solid coupled models introduce greater heterogeneity of myocardial work than was observed in equivalent solid only models. A patient study was undertaken using a myocardial geometry constructed using image data from an LVAD implant recipient. A series of different LVAD flow regimes were tested. It was found that the opening of the aortic valve had a homogenising effect on the spatial variation of work, indicating that the synchronisation of LVAD outflow with the cardiac cycle is more important if the valve remains shut. Additionally, increasing LVAD outflow during systole and decreasing it during diastole led to improved mixing of blood in the ventricular cavity – compared with either the inverse, or holding outflow constant. Validation of these findings has the potential to impact the treatment protocols of LVAD patients.

L'insuffisance cardiaque (IC) chronique représente la pathologie la plus fréquente nécessitant l'hospitalisation chez les patients de plus de 65 ans. La mortalité à 5 ans est estimée à plus de 50% et les enjeux en terme d’économie et de santé publique sont immenses. Parmi de nombreuses étiologies, les cardiopathies ischémiques sont la cause principale de l’IC. Sur les quinze dernières années, de nombreuses études précliniques et cliniques ont confirmé le potentiel thérapeutique des cellules souches d’améliorer la fonction cardiaque et d’atténuer le remodelage ventriculaire. Néanmoins, beaucoup de questions fondamentales liées à la thérapie régénératrice avec les cellules souches restent à résoudre. Parmi les raisons expliquant l'inefficacité de la thérapie cellulaire figurent l'intégration et la survie compromises des cellules greffées dans un microenvironnement défavorable au sein de tissus infarcis ainsi que la présence d'inflammation, de stress oxydatif, d'hypoxie sévère et de privation des nutriments. Une des approches pour améliorer la thérapie cellulaire serait d’adapter le milieu de culture des cellules in vitro en terme de concentration en oxygène afin qu’il soit plus proche des conditions in vivo. Notre étude a bien montré que le préconditionnement des cellules souches mésenchymateuses (CSMs) à l’hypoxie permettait de promouvoir la croissance cellulaire tout en gardant leur potentiel de différenciation trilignée. De plus, notre étude in vivo montrait que les CSMs cultivées en hypoxie, par rapport à celles cultivées en normoxie, présentaient un meilleur potentiel thérapeutique : amélioration de la viabilité dans la zone infarcie, augmentation de la contractilité intrinsèque et favorisation du processus d’angiogénèse, etc. Force est de constater que la récupération de la fonction cardiaque sous dispositifs d'assistance ventriculaire (bridge to recovery) pose un jalon dans le traitement de l'insuffisance cardiaque. Le phénomène « bridge to recovery » nous a permis d'approfondir la connaissance sur la physiopathologie du remodelage ventriculaire, qui était considéré comme un processus unidirectionnel. Cependant, plusieurs controverse existent sur la stratégie ‘Bridge to Recovery’. Une des questions les plus soulevées est s'il y a une limite à la durée et à l'intensité de la décharge ventriculaire afin d'éviter ses effets secondaires. Pour simuler les décharges mécaniques ventriculaires d'intensités différentes, nous avons mis au point deux modèles de transplantation cardiaque hétérotopique (TCH), cœur seul ou cœur-poumon, mimant respectivement la décharge complète et la décharge partielle. Notre étude montrait que la décharge mécanique résultait d’une atrophie myocardique, d’une réduction du métabolisme glucidique, d’une fibrose cardiaque et d’une altération de fonction cardiaque diastolique. Les effets étaient tous dépendants des intensités de décharge. Notre travail s'insère dans la thématique générale du laboratoire, qui est de développer un programme de recherche sur les approches thérapeutiques innovantes pour traiter l'infarctus du myocarde et l'IC chronique. Dans la première partie de notre projet, nous avons cherché à clarifier les effets de l'injection intramyocardique de CSMs d'origine médullaire dans la zone infarcie sur la perfusion et la fonction cardiaque (étude n°1). Nous avons ensuite étudié l'impact de la culture cellulaire en hypoxie des CSMs dérivées de moelle osseuse sur leurs caractéristiques biologiques et leur potentiel thérapeutique (étude n°2). Enfin, nous avons caractérisé les effets de décharges mécaniques d'intensités différentes sur le remodelage ventriculaire du cœur sain, sur le plan morphologique, fonctionnel et métabolique (étude n°3) / Heart failure (HF) represents one of the most frequent disease requiring hospitalization in the old population (>65 years old). The 5-year survival rates associated with heart failure are less than 50% and it results in a huge cost on social economy and public health. Ischemic heart diseases represent one of the most frequent etiologies of the heart failure. Over the last fifteen years, many preclinical and clinical studies have confirmed the therapeutic potential of stem cells to improve heart function and reduce ventricular remodeling. The failure of cell therapy can be ascribed to some extent to the poor integration and compromised survival of grafted cells in an unfavorable microenvironment in infarcted tissue which is complicated by the presence of inflammation, oxidative stress, hypoxia and severe deprivation of nutriments. Furthermore, bone marrow stem cells are physiologically located in a hypoxic environment. The adaptation of the in vitro culture medium, in terms of oxygen concentration, to the in vivo natural niche as well as the targeted area, might be one of solutions to improve the efficacy of cell therapy. One of our studies has demonstrated that preconditioning of mesenchymal stem cells (MSCs) with hypoxia could promote cell proliferation without altering the differentiation potential. What’s more, our in vivo study showed that hypoxia-preconditioned MSCs, compared with those cultured in normoxia, presented with better therapeutic efficiency, such as improvement of the myocardial viability in the infarcted area, increase of intrinsic contractility and favoring the processes of angiogenesis. The recovery of cardiac function with ventricular assist devices (bridge to recovery) is a milestone in the treatment of heart failure. The phenomenon "bridge to recovery" has enabled us to deepen the knowledge on the physiopathology of ventricular remodeling, which was considered to be a one-way process. However, the strategy of ‘Bridge to Recovery’ causes many controversies. One of the arisen questions is if there exists a limit in terms of the duration and intensity regarding the mechanical unloading in order to minimize its secondary complications. To simulate ventricular mechanical unloading of different intensities, we have developed two models of heterotopic heart transplantation (TCH), namely, heterotopic heart transplantation (HHT) and heterotopic heart-lung transplantation to simulate complete and partial unloading, respectively. Our study revealed that mechanical unloading resulted in myocardial atrophy, cardiac fibrosis and diastolic dysfunction. These secondary effects were dependent on the intensity of unloading. Our work fits into the general theme of the laboratory, which is to develop a research program on innovative therapeutic approaches to treat myocardial infarction and chronic heart failure. In the first part of our study, we sought to clarify the effects of bone marrow-derived MSCs following intramyocardial injection on the perfusion and function of the infarcted myocardium (study 1). We then investigated the impact of long-term hypoxic culture on the biological characteristics and therapeutic potential of MSCs (study 2). Finally, we explored the effects of mechanical unloading of different intensities on the structure, function and metabolism of healthy myocardium (Study 3)

Le choc cardiogénique (CC) est un état d’hypoperfusion critique des organes cibles causé par une dysfonction profonde du myocarde. Cette situation dangereuse et dynamique nécessite des interventions rapides de la part d'une équipe multidisciplinaire pour sauver la vie du patient, mais le risque de décès demeure encore très élevé́. Actuellement, l’utilité des dispositifs d’assistance ventriculaire percutanés (DAVp) pour traiter le CC n’est pas suffisamment étudiée. Concevoir un modèle artificiel de CC pourrait faciliter la compréhension du CC ainsi que le développement de nouveaux DAVp. Au cours de ce projet, nous nous sommes premièrement intéressés au sujet en synthétisant les données cliniques sur l’utilisation des DAVp dans un contexte de CC compliquant un infarctus du myocarde (IM-CC) sous forme de revues systématiques. Par la suite, nous avons conçu un projet expérimental visant à démontrer la faisabilité d’un modèle animal stable d’IM-CC en induisant par méthode percutanée un infarctus étendu de la paroi antérieure in vivo chez le porc qui pourrait être utilisé pour fournir des données physiologiques supportant la création d’un modèle artificiel d’haute-fidélité. L’état de CC stable a été confirmé par une combinaison de données hémodynamiques et de laboratoire et l’ampleur de l’infarctus a été validée par des techniques de coloration ex vivo. Ayant atteint notre objectif primaire de ≥50% de survie suite à l’infarctus et l’induction d’un état de CC chez 50% des cochons, nous concluons que notre modèle animal est suffisamment stable pour procéder à la prochaine étape de notre programme. / Cardiogenic shock (CS) is a state of critical end-organ hypoperfusion resulting from profound myocardial dysfunction that is both dangerous and dynamic and requires rapid, coordinated multidisciplinary care in order to prevent mortality. However, despite appropriate medical management, the risk of early mortality remains high. Percutaneous mechanical support devices (pMCS) offer the promise of correcting pump dysfunction, but their clinical utility in CS remains debated and understudied. Developing a reliable synthetic model of CC could both improve our understanding of CS and accelerate the development of the next generation of pMCS devices. In this work, we first present the results of two systematic reviews of the comparative effectiveness of currently available pMCS devices in the setting of post-acute myocardial infarction CS (AMI-CS). We then sought to demonstrate the feasibility of creating a stable animal model of AMI-CS by inducing an anterior myocardial infarction in vivo in a pig in order to generate the physiologic data required to develop a high-fidelity three-dimensional AMI-CS simulator. The CS state was confirmed by a combination of hemodynamic and laboratory data and the size of the infarct was confirmed thereafter by ex vivo staining techniques. We achieved our primary goal of ≥50% short-term survival post-infarction and induction of a CS state in 50% and therefore conclude that our model is sufficiently stable to warrant proceeding with the next phase of our program